MX2012003046A - Treatment of cancer. - Google Patents

Treatment of cancer.

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Publication number
MX2012003046A
MX2012003046A MX2012003046A MX2012003046A MX2012003046A MX 2012003046 A MX2012003046 A MX 2012003046A MX 2012003046 A MX2012003046 A MX 2012003046A MX 2012003046 A MX2012003046 A MX 2012003046A MX 2012003046 A MX2012003046 A MX 2012003046A
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MX
Mexico
Prior art keywords
conjugate
cdp
cancer
composition
particle
Prior art date
Application number
MX2012003046A
Other languages
Spanish (es)
Other versions
MX342709B (en
Inventor
Yun Yen
Thomas Schluep
John Ryan
Davis Mark
James C Oliver
Original Assignee
Cerulean Pharma Inc
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Publication date
Application filed by Cerulean Pharma Inc filed Critical Cerulean Pharma Inc
Publication of MX2012003046A publication Critical patent/MX2012003046A/en
Publication of MX342709B publication Critical patent/MX342709B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Abstract

Provided are methods relating to compositions that include a CDP- topoisomerase inhibitor, e.g., a CDP-camptothecin or camptothecin derivative conjugate, e.g., CRLX101.

Description

TREATMENT AGAINST CANCER Background of the Invention Administration of drugs and dosing of small molecule therapeutics, such as camptothecin, can be problematic due to several aspects, including half-life, toxicity, distribution, etc.
Brief Description of the Invention In one aspect, the disclosure presents a method for treating a proliferative disorder, eg, cancer, in a subject. The method includes: provide an initial administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a conjugate, particle or camptothecin composition bound to the CDP or a conjugate, particle or composition derived from camptothecin, eg, a conjugate , particle or composition of camptothecin bound to the CDP or a conjugate, particle or composition derived from camptothecin described herein, eg, CRLX101, to said subject in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2 , 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2 , 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2 , 29 mg / m2 or 30 mg / m2, (wherein said dosage is expressed in mg of the drug, as opposed to mg of the conjugate) and optionally, providing one or more subsequent administrations of said conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a conjugate, particle or composition of camptothecin bound to the CDP or a conjugate, particle or composition derived from camptothecin , for example, a conjugate, particle or composition of camptothecin bound to the CDP or a conjugate, particle or camptothecin derivative composition described herein, for example, CRLX101, in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2, where each subsequent dosage is provided, independently, between 9, 10, 11, 12, 13, 14, 15 or 16 days after the previous administration, for example, the initial administration, to treat Thus, the proliferative disorder.
In one embodiment, the dosage of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15 or 20 administrations is the same.
In one embodiment, the time between at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15 or 20 administrations is the same.
In one embodiment, each subsequent administration is administered 12-16, for example, 14, days after the previous administration.
In one embodiment, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 50 or 100 administrations are administered to said subject.
In one embodiment, the drug is provided at 12-17 mg / m2 / administration, eg, 12 -15 mg / m2 / adminstration.
In one embodiment, the drug is provided at 18-60 mg / m2 / month, for example, 18 -30 mg / m2 / month, 24-30 mg / m / month or 36-60 mg / m2 / month.
In one embodiment, the conjugate includes an inhibitor of topoisomerase I and / or an inhibitor of topoisomerase II. In one embodiment, the conjugate includes a topoisomerase I inhibitor or combination of topoisomerase I inhibitors, for example, camptothecin, irinotecan, SN-38, topotecan, lamelarin D, and derivatives thereof. In one embodiment, the conjugate includes a topoisomerase II inhibitor or a combination of topoisomerase II inhibitors, e.g., eptoposide, tenoposide, doxorubicin, and derivatives thereof. In one embodiment, the conjugate includes a combination of one or more inhibitors of topoisomerase I and one or more inhibitors of topoisomerase II. In one embodiment, the conjugate of the topoisomerase inhibitor bound to the CDP is a camptothecin conjugate or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate or camptothecin derivative linked to the CDP described herein, eg, CRLX101 .
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin or camptothecin derivative linked to the CDP, a camptothecin conjugate, particle or composition of camptothecin attached to the CDP described in present, for example, CRLX101, is administered by intravenous administration for a period equal to or less than about 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes or 180 minutes. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a conjugate, particle or camptothecin composition or derivative of camptothecin bound to the CDP described herein, for example, CRLX101, is administered in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2 , 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2 , 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2 by intravenous administration during a period equal to or less than about 30 minutes, 45 minutes, 60 minutes or 90 minutes, for example, a period equal to or less than 30 minutes, 45 minutes or 60 minutes.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, camptothecin or a camptothecin derivative linked to the CDP, a camptothecin conjugate, particle or composition of camptothecin attached to the CDP described in present, for example, CRLX101, is administered by intravenous administration for a period of about 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 27 hours or 30 hours. In one embodiment, the conjugate, particle or composition of the topoisonerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, for example, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2 , 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2 by intravenous administration during a period of about 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 27 hours or 30 'hours. Preferably, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a conjugate, particle or camptothecin composition or derivative of camptothecin bound to the CDP described herein, for example, CRLX101, is administered in a dosage of 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2 , 21 mg / rn2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2 by intravenous administration for a period of about 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 27 hours or 30 hours.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, the conjugate, particle or camptothecin composition or Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2 or 14 mg / m2 twice; per day and, optionally, one or more subsequent administrations of said conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a conjugate, particle or composition of camptothecin bound to the CDP or conjugate, particle or composition derived from camptothecin, for example, a conjugate, particle or composition of camptothecin linked to the CDP or conjugate, particle or composition derived from camptothecin described herein, for example, CRLX101, is provided in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2 or 14 mg / m2 twice a day, where each subsequent administration is provided, independently, between 9, 10, 11, 12, 13, 14, 15 or 16 days after the previous administration, for example, the initial one, to treat the proliferative disorder. In one embodiment, the second daily dose is provided 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20 hours after the initial daily dose.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2, for example, with the same dosage as the initial dosage, wherein each subsequent administration is administered, independently, 12-16, for example, 14, days after the previous administration, for example, the initial administration and the cancer is, for example, cancer of lung, for example, non-small cell lung cancer and / or small cell lung cancer (e.g., non-small cell lung cancer of squamous cell or small cell lung cancer of squamous cell). In one embodiment, lung cancer is insensitive, unruly or resistant to a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin) and / or a taxane (e.g., docetaxel, paclitaxel, larotaxel or cabazitaxel).
In one embodiment, the method includes an initial administration of CRLX101 to said subject at a dosage of 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2, for example, with the same dosage as the initial dosage, where each subsequent administration is administered, independently, 12-16, for example, 14, days after the previous administration, for example, the initial administration, and the cancer is, for example, lung cancer, for example, non-small cell lung cancer and / or cancer of small cell lung (e.g., non-small cell lung cancer of squamous cell or small cell lung cancer of squamous cell). In one embodiment, lung cancer is insensitive, unruly or resistant to a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin) and / or a taxane (e.g., docetaxel, paclitaxel, larotaxel or cabazitaxel).
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2, for example, with the same dosage as the initial dosage, wherein each subsequent administration is administered, independently, 12-16, for example, 14, days after the previous administration, for example, the initial administration, and cancer is, for example, ovarian cancer. In one embodiment, ovarian cancer is insensitive, unruly or resistant to a platinum-based agent (eg, carboplatin, cisplatin, oxaliplatin). In one embodiment, CRLX101 is administered by intraperitoneal administration.
In one embodiment, the method includes an initial administration of CRLX101 to said subject at a dosage of 16 mg / fn2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2, for example, with the same dosage as the dosage initial, wherein each subsequent administration is administered, independently, 12-16, for example, 14, days after the previous administration, for example, the initial administration, and the cancer is, for example, ovarian cancer. In one embodiment, ovarian cancer is insensitive, unruly or resistant to a platinum-based agent (eg, carboplatin, cisiplatine, oxaliplatin). In one embodiment, CRLX101 is administered by intraperitoneal administration.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2, for example, with the same dosage as the initial dosage, wherein each subsequent administration is administered, independently, 12-16, for example, 14, days after the previous administration, for example, the initial administration, and the cancer is, for example, gastric cancer, for example, gastro-esophageal, upper gastric or lower gastric cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject at a dosage of 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2, for example, with the same dosage as the dosage initial, where each subsequent administration is administered, independently, 12-16, for example, 14, days after the previous administration, for example, the initial administration, and the cancer is, for example, gastric cancer, for example Gastroesophageal, upper gastric or lower gastric cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 12 mg / iin2, 13 mg / m2, 14 mg / m2 or 15 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 12 mg / m2, 13 mg / m2, 14 mg / m2 or 15 mg / m2, for example, with the same dosage as the initial dosage, wherein each subsequent administration is administered, independently, 12-16, for example, 14, days after the previous administration, for example, the initial administration, and he cancer is, for example, pancreatic cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject at a dosage of 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2, for example, with the same dosage as the dosage initial, where each subsequent administration is administered, independently, 12-16, for example, 14, days after the previous administration, for example, the initial administration, and the cancer is, for example, pancreatic cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2, for example, with the same dosage as the initial dosage, wherein each subsequent administration is administered, independently, 12-16, for example, 14, days after the previous administration, for example, the initial administration, and the cancer is, for example, Colorectal cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject at a dosage of 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2, for example, with the same dosage as the dosage initial, where each subsequent administration is administered, independently, 12-16, for example, 14, days after the previous administration, for example, the initial administration, and the cancer is, for example, colorectal cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 12 mg / tin2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2, for example, with the same dosage as the initial dosage, wherein each post-administration administration is administered, independently, 12-16, for example, 14, days after the previous administration, for example, the initial administration, and cancer is, for example, breast cancer, for example, estrogen receptor positive breast cancer, estrogen receptor negative breast cancer, HER-2 positive breast cancer, HER-2 negative breast cancer, triple negative breast cancer or breast cancer inflammatory.
In one embodiment, the method includes an initial administration of CRLX101 to said subject at a dosage of 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2, for example, with the same dosage as the dosage initial, where each subsequent administration is administered, in a manner independent, 12-16, for example, 14, days after the previous administration, for example, the initial administration, and the cancer is, for example, breast cancer, for example, estrogen receptor positive breast cancer, cancer of negative estrogen receptor breast, HER-2 positive breast cancer, negative HER-2 breast cancer, triple negative breast cancer or inflammatory breast cancer.
In one embodiment, cancer is a cancer described herein. For example, cancer can be a bladder cancer (including accelerated and metastatic bladder cancer), breast cancer (eg, estrogen receptor positive breast cancer, estrogen receptor negative breast cancer, HER breast cancer). -2 positive, HER-2 negative breast cancer, triple negative breast cancer, inflammatory breast cancer), colon (including colorectal cancer), kidney, liver, lung cancer (including small cell lung cancer and lung cancer) non-small cell (including adenocarcinoma, squamous cell carcinoma, bronchioalveolar carcinoma, and large cell carcinoma)), genitourinary tract, eg, ovarian (including cancers of the fallopian, endometrium, and peritoneal), cervix, prostate, and testicles, lymphatic system , rectum, larynx, pancreas (including exocrine pancreatic carcinoma), stomach (for example, gastro-esophageal, gastric or upper gastric cancer), gastrointestinal cancer stinal (eg, anal cancer), gallbladder, thyroid, lymphoma (eg, Burkitt's lymphoma, Hodgkin's or otherwise), leukemia (eg, acute myeloid leukemia), Ewing's sarcoma, nasoesophageal cancer, nasopharyngeal cancer, cancers neuronal and glial cells (eg, glioblastoma multiforme), and head and neck. Preferred cancers include breast cancer (e.g., metastatic or locally advanced breast cancer), prostate cancer (e.g., hormone-refractory prostate cancer), renal cell carcinoma, lung cancer (e.g., lung cancer) small cell and non-small cell lung cancer (including adenocarcinoma, squamous cell carcinoma, bronchioalveolar carcinoma, and large cell carcinoma), pancreatic cancer, gastric cancer (eg, gastroesophageal, upper gastric, or lower gastric cancer), colorectal cancer, cancer of squamous cells of the head and neck, ovarian cancer (eg, advanced ovarian cancer, rebel ovarian cancer or resistant to a platinum-based agent), lymphoma (eg, Burkitt's lymphoma, Hodgkin's or non-Hodgkin's lymphoma), leukemia (for example, acute myeloid leukemia) and gastrointestinal cancer.
In one embodiment, the cancer is ovarian cancer, colorectal, breast, lung, lymphoma or gastric cancer. In one embodiment, the cancer is a cancer other than pancreatic cancer, renal cell carcinoma and / or lung cancer (e.g., non-small cell lung cancer and / or small cell lung cancer). In one embodiment, cancer is a cancer other than pancreatic cancer, renal cell carcinoma, lung cancer (for example, non-small cell lung cancer and / or small cell lung cancer) and / or ovarian cancer.
In one embodiment, the subject has not been administered a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, eg, CRLX101, prior to the initial administration.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to CDP is administered as a first-line treatment for cancer.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered as a second, third or fourth line treatment for cancer. In one embodiment, the cancer is responsive to one or more of the chemotherapeutic agents, for example, a platinum-based agent, a taxane, an alkylating agent, an anthracycline (eg, doxorubicin (eg, liposomal doxorubicin)), a antimetabolite and / or a vinca alkaloid. In one embodiment, the cancer is insensitive, unruly or resistant to one or more chemotherapeutic agents, for example, a platinum-based agent, a taxane, an alkylating agent, an antimetabolite and / or a vinca alkaloid. In one embodiment, the cancer is, for example, ovarian cancer, and ovarian cancer is insensitive, unruly or resistant to a platinum-based agent (eg, carboplatin, cisplatin, oxaliplatin), a taxane (e.g., paclitaxel). , docetaxel, larotaxel, cabazitaxel) and / or an anthracycline (eg, doxorubicin (eg, liposomal doxorubicin)). In one embodiment, the cancer is, for example, colorectal cancer, and the cancer is insensitive, unruly or resistant to an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) and a pyrimidine analogue (e.g. , capecitabine, citrarabine, gemcitabine, 5FU)) and / or a platinum-based agent (eg, carboplatin, cisplatin, oxaliplatin). In one embodiment, the cancer is, for example, lung cancer, and the cancer is insensitive, unresponsive, or resistant to a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel), a platinum-based agent (e.g., carboplatin). , cisplatin, oxaliplatin), a vinca alkaloid (eg, vinblastine, vincristine, vindesine, vinorelbine), an inhibitor of the vascular endothelial growth factor (VEGF) pathway, an inhibitor of the epidermal growth factor pathway ( EGF) and / or an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine raltitrexed) and a pyrimidine analogue (e.g., capecitabine, citrarabine, gemcitabine, 5FU)). In one embodiment, the cancer is, for example, breast cancer, and the cancer is insensitive, unruly or resistant to a taxane (eg, paclitaxel, docetaxel, larotaxel, cabazitaxel), an inhibitor of the endothelial growth factor pathway. vascular (VEGF), an anthracycline (eg, daunorubicin, doxorubicin (eg, doxorubicin) liposomal), epirubicin, valrubicin, idarubicin), a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin) and / or an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) and an analogue pyrimidine (for example, capecitabine, citrarabine, gemcitabine, 5FU)). In one embodiment, the cancer is, for example, gastric cancer, and the cancer is insensitive, unruly or resistant to an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) and a pyrimidine analogue (e.g. , capecitabine, citrarabine, gemcitabine, 5FU)) and / or a platinum-based agent (eg, carboplatin, cisplatin, oxaliplatin).
In one embodiment, the subject has ovarian cancer that is insensitive, unruly or resistant to a platinum-based agent, and the subject is administered a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a conjugate. , particle or composition of the topoisomerase inhibitor bound to the CDP described herein. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor is administered in combination with doxorubicin (eg, liposomal doxorubicin). In one embodiment, doxorubicin (eg, liposomal doxorubicin) is administered at a dose of about 20 mg / m2, about 30 mg / m2 or about 40 mg / m2, every 24, 25, 26, 27, 28, 29, 30 or 31 days, for example, 28 days. In one embodiment, when the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with doxorubicin (eg, liposomal doxorubicin), the dose at which the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP is administered is 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30% lower than the dose described here.
In one embodiment, the cancer has been sensitized to a topoisomerase inhibitor, e.g., the subject has received radiation and / or the subject has received a phosphatase inhibitor (e.g., okadaic acid) prior to administration of the conjugate, particle or topoisomerase inhibitor composition bound to the CDP. In one embodiment, the cancer is sensitized to topoisomerase inhibitors, for example, the subject receives radiation in combination with the administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP and / or the subject is administered an inhibitor. of the phosphatase (eg, okadaic acid) in combination with the administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP. In one embodiment, the cancer is sensitized or sensitized to topoisomerase inhibitors and the cancer is a cancer of glial cells (eg, glioblastoma multiforme) or cancer of the head and neck.
In one embodiment, the conjugate, particle or composition is administered in combination with one or more additional chemotherapeutic agents, for example, a chemotherapeutic agent (such as, an angiogenesis inhibitor) or combination of chemotherapeutic agents described herein. In one embodiment, the conjugate, particle or composition is administered in combination with one or more of: a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin), a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel) , a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine), an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) and a pyrimidine analogue (e.g., 5FU, capecitabine, citrarabine, gemcitabine)), an alkylating agent (eg, cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide), an inhibitor of the vascular endothelial growth factor (VEGF) pathway, an inhibitor of poly ADP-ribose polymerase (PARP) ) and an mTOR inhibitor. In one embodiment, when the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with an additional chemotherapeutic agent, the dose at which the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP is administered. it is 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30% less than the dose described here.
In one embodiment, the method further comprises administering to said subject a treatment that reduces one or more side effects associated with the administration of a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, for example, a treatment described in I presented.
In one aspect, the disclosure presents a method for treating a proliferative disorder, eg, cancer, in a subject, e.g., a human subject. The method includes: provide an initial administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or camptothecin derivative or camptothecin derivative attached to the CDP, eg, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, to said subject in a dosage of 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2, 30 mg / m2, 31 mg / m2, 32 mg / m2, 33 mg / m2, 34 mg / m2, 35 mg / m2 or 36 mg / m2 (wherein said dosage is expressed in mg of the drug, as opposed to mg of the conjugate) and optionally, providing one or more subsequent administrations of said conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or camptothecin composition or camptothecin derivative attached to the CDP, eg, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2, 30 mg / m2, 31 mg / m2, 32 mg / m2, 33 mg / m2, 34 mg / m2, 35 mg / m2 or 36 mg / m2, where each subsequent administration is provided, independently between 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 days after the previous administration, for example, initial, to treat the proliferative disorder.
In one embodiment, the dosage of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15 or 20 administrations is the same.
In one modality, the time between at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15 or 20 administrations is the same.
In one embodiment, each subsequent administration is administered 19-23, for example, 21 or 25-29, for example, 27 or 28 days after the previous administration.
In one embodiment, said subject is administered to menps 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 50 or 100 administrations.
In one embodiment, the drug is provided at 18-60 mg / m2 / month, eg, 18-30 mg / m2 / month or 36-60 mg / m / month. In one embodiment, when the drug is provided in combination with one or more additional chemotherapeutic agents, for example, a chemotherapeutic agent described herein, the drug is provided at 6-12 mg / m2 / month.
In one embodiment, the conjugate includes an inhibitor of topoisomerase I and / or an inhibitor of topoisomerase II. In one embodiment, the conjugate includes a topoisomerase I inhibitor or combination of topoisomerase I inhibitors, for example, camptothecin, irinotecan, SN-38, topotecan, lamelarin D, and derivatives thereof. In one embodiment, the conjugate includes an inhibitor of topoisomerase II or a combination of inhibitors; of topoisomerase II, for example, eptoposide, tenoposide, doxorubicin and derivatives thereof. In one embodiment, the conjugate includes a combination of one or more inhibitors of topoisomerase I and one or more inhibitors of topoisomerase II. In one embodiment, the conjugate of the topoisomerase inhibitor bound to the CDP is a camptothecin conjugate or camptothecin derivative linked to the CDP, for example, a camptothecin conjugate or camptothecin derivative linked to the CDP described herein, for example, CRLX101.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, camptothecin or a camptothecin derivative linked to the CDP, a camptothecin conjugate, particle or composition of camptothecin attached to the CDP described in present, for example, CRLX101, is administered by intravenous administration for a period equal to or less than about 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes or 180 minutes. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, for example, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in a dosage of 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / im2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2, 30 mg / im2, 31 mg / m2, 32 mg / m2, 33 mg / m2, 34 mg / m2, 35 mg / m2 or 36 mg / m2 by intravenous administration for a period equal to or less than about 30 minutes, 45 minutes, 60 minutes or 90 minutes, for example, a period equal to or less than 30 minutes, 45 minutes or 60 minutes.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin or camptothecin derivative linked to the CDP, a camptothecin conjugate, particle or composition or derived from camptothecin attached to the CDP described in present, for example, CRLX101, is administered by intravenous administration for a period of about 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 27 hours or 30 hours. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in a dosage of 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2, 30 mg / m2 m2, 31 mg / m2, 32 mg / m2, 33 mg / m2, 34 mg / m2, 35 mg / m2 or 36 mg / m2 by intravenous administration for a period of about 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 27 hours or 30 hours.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, the conjugate, particle or camptothecin composition or Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2 or 14 mg / m2 twice a day and, optionally, one or more subsequent administrations of said conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a conjugate , particle or composition of camptothecin bound to the CDP or conjugate, particle or composition derived from camptothecin, for example, a conjugate, particle or camptothecin composition bound to the CDP or conjugate, particle or composition derived from camptothecin described herein, for example, CR LX101, is provided in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2 or 14 mg / m2 twice a day, where each subsequent administration is provided, independently, between 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 20 or 31 days after the previous administration, for example, the initial administration, to treat thus the proliferative disorder. In one embodiment, the second daily dose is provided 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20 hours after the initial daily dose.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mgi / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2, for example, with the same dosage as the initial dosage, where each subsequent administration is provided, independently, 19-22, for example, 21, days after the previous administration, for example, the initial administration, and the cancer is, for example, lung cancer, for example, non-small cell lung cancer and / or small cell lung cancer (eg, non-small cell lung cancer of squamous cell or small cell lung cancer of squamous cell). In one embodiment, lung cancer is insensitive, unruly or resistant to a platinum-based agent (eg, carboplatin, cisplatin, oxaliplatin) and / or a taxane (docetaxel, paclitaxel, larotaxel or cabazitaxel).
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2, for example, with the same dosage as the initial dosage, where each subsequent administration is provided, independently 19-22, for example, 21, days after the previous administration, for example, initial, and cancer is, for example, ovarian cancer. In one embodiment, ovarian cancer is insensitive, unruly or resistant to a platinum-based agent (eg, carboplatin, cisplatin, oxaliplatin). In one embodiment, CRLX101 is administered by intraperitoneal administration.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2, for example, with the same dosage as the initial dosage, where each subsequent administration is provided, independently, 19-22, for example, 21, days after the previous administration, for example, the initial administration, and the cancer is, for example, gastric cancer, for example, gastroesophageal, upper gastric or lower gastric cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2, for example, with the same dosage as the initial dosage, where each subsequent administration is provided, independently, 19-22, for example, 21, days after the previous administration, for example, the initial administration, and the cancer is, for example, pancreatic cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2, for example, with the same dosage as the initial dosage, where each subsequent administration is provided, independently, 19-22, for example, 21, days after the previous administration, for example, the initial administration, and the cancer is, for example, colorectal cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2 or 18 mg / m2, for example, with the same dosage as the initial dosage, where each subsequent administration is provided, independently, 19-22, for example, 21, days after the previous administration, for example, the initial administration, and the cancer is, for example, breast cancer, for example, estrogen receptor positive breast cancer , estrogen receptor negative breast cancer, HER-2 positive breast cancer, negative HER-2 breast cancer, triple negative breast cancer or inflammatory breast cancer.
In one embodiment, cancer is a cancer described herein. For example, the cancer may be a bladder cancer (including accelerated and metastatic bladder cancer), mgma (e.g., estrogen receptor positive breast cancer, estrogen receptor negative breast cancer, HER breast cancer). -2 positive, HER-2 negative breast cancer, triple breast cancer negative, inflammatory breast cancer), colon (including colorectal cancer), kidney, liver, lung cancer (including small cell lung cancer and non-small cell lung cancer (including adenocarcinoma, squamous cell carcinoma, bronchioalveolar carcinoma and large cell carcinoma)), genitourinary tract, eg, ovarian (including cancers of the fallopian, endometrium and peritoneal), cervix, prostate and testes, lymphatic system, rectum, larynx, pancreas (including exocrine pancreatic carcinoma), stomach (e.g., gastroesophageal, upper gastric or lower gastric cancer), gastrointestinal cancer (e.g. anal cancer), gall bladder, thyroid, lymphoma (e.g., Burkitt's lymphoma, Hodgkin's or non-Hodgkin's lymphoma), leukemia (e.g. acute myeloid leukemia), Ewing's sarcoma, nasoesophageal cancer, nasopharyngeal cancer, neuronal cancers, and glial cells (eg, glioblastoma multiforme), and za and neck. Preferred cancers include breast cancer (e.g., locally advanced or metastatic breast cancer), prostate cancer (e.g., hormone-refractory prostate cancer), renal cell carcinoma, lung cancer (e.g., lung cancer) small cell and non-small cell lung cancer (including adenocarcinoma, squamous cell carcinoma, bronchioalveolar carcinoma, and large cell carcinoma), pancreatic cancer, gastric cancer (eg, gastroesophageal, upper gastric, or lower gastric cancer), colorectal cancer, cancer of squamous cells of the head and neck, ovarian cancer (for example, advanced ovarian cancer, rebel ovarian cancer or resistant to a platinum-based agent), lymphoma (e.g., Burkitt's lymphoma, Hodgkin's or non-Hodgkin's lymphoma), leukemia (e.g., acute myeloid leukemia), and gastrointestinal cancer.
In one embodiment, the cancer is ovarian cancer, colorectal, breast, lung, lymphoma or gastric cancer. In one embodiment, the cancer is a cancer other than pancreatic cancer, renal cell carcinoma and / or lung cancer (e.g., non-small cell lung cancer). In one embodiment, cancer is a cancer other than pancreatic cancer, renal cell carcinoma, lung cancer (e.g., non-small cell lung cancer) and / or ovarian cancer.
In one embodiment, the subject has not been administered a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, eg, CRLX101, prior to the initial administration.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to CDP is administered as a first-line treatment for cancer.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered as a second, third or fourth line treatment for cancer. In one embodiment, the cancer is responsive to one or more of the chemotherapeutic agents, for example, a platinum-based agent, a taxane, an alkylating agent, an antimetabolite and / or a vinca alkaloid. In one embodiment, the cancer is insensitive, unruly or resistant to one or more chemotherapeutic agents, for example, platinum-based agent, a taxane, an alkylating agent, an anthracycline (eg, doxorubicin (eg, liposomal doxorubicin)), an antimetabolite and / or a vinca alkaloid. In a modality, cancer is, for example, ovarian cancer, and ovarian cancer is insensitive, unruly or resistant to a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin), a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel) and / or an anthracycline (eg, doxorubicin (eg, liposomal doxorubicin)). In one embodiment, the cancer is, for example, colorectal cancer, and the cancer is insensitive, unruly or resistant to an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) and a pyrimidine analogue (e.g. , capecitabine, citrarabine, gemcitabine, 5FU)) and / or a platinum-based agent (eg carboplatin, cisplatin, oxaliplatima). In one embodiment, the cancer is, for example, lung cancer, and the cancer is insensitive, unresponsive, or resistant to a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel), a platinum-based agent (e.g., carboplatin). , cisplatin, oxaliplatin), a vinca alkaloid (for example, vinblastine, vincristine, vindesine, vinorelbine), an inhibitor of the growth factor pathway vascular endothelial (VEGF), an inhibitor of the epidermal growth factor (EGF) pathway and / or an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) and a pyrimidine analogue (e.g., capecitabine , citrarabine, gemcitabine, 5FU)). In one embodiment, the cancer is, for example, breast cancer, and the cancer is insensitive, unresponsive or resistant to a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel), an inhibitor of the endothelial growth factor pathway vascular (VEGF), an anthracycline (eg, daunorubicin, doxorubicin (eg, liposomal doxorubicin), - epirubicin, valrubicin, idarubicin), a platinum-based agent (eg, carboplatin, cisplatin, oxaliplatin) and / or an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) and a pyrimidine analogue (e.g., capecitabine, citrarabine, gemcitabine, 5FU)). In one embodiment, the cancer is, for example, gastric cancer, and the cancer is insensitive, unruly or resistant to an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) and a pyrimidine analogue (e.g. , capecitabine, citrarabine, gemcitabine, 5FU)) and / or a platinum-based agent (eg, carboplatin, cisplatin, oxaliplatin).
In one embodiment, the subject has ovarian cancer that is insensitive, unruly or resistant to a platinum-based agent, and the subject is administered a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a conjugate. , particle or composition of the topoisomerase inhibitor bound to the CDP described herein. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with doxorubicin (eg, liposomal doxorubicin). In one embodiment, doxorubicin (eg, liposomal doxorubicin) is administered at a dose of about 20 mg / m2, about 30 mg / m2 or about 40 mg / m2, every 24, 25, 26, 27, 28, 29, 30 or 31 days, for example, 28 days. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP described herein is administered in a dose and / or dosing regimen described herein and doxorubicin (eg, liposomal doxorubicin) is administered at a dose of about 20 mg / m2, about 30 mg / m2 or about 40 mg / m2, every 24, 25, 26, 27 , 28, 29, 30 or 31 days, for example, 28 days. In one embodiment, when the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with doxorubicin (eg, liposomal doxorubicin), the dose at which the conjugate, particle or composition of the inhibitor is administered. Topoisomerase attached to the CDP is 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30% lower than the dose described herein.
In one embodiment, the cancer has been sensitized to topoisomerase inhibitors, eg, the subject has received radiation and / or the subject has received a phosphatase inhibitor (eg, okadaic acid) prior to administration of the conjugate, particle or topoisomerase inhibitor composition bound to the CDP. In one embodiment, the cancer has been sensitized to topoisomerase inhibitors, for example, the subject receives radiation in combination with the administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP and / or the subject is administered a phosphatase inhibitor (eg, okadaic acid) in combination with the administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP. In one embodiment, the cancer is sensitized or sensitized to topoisomerase inhibitors and the cancer is a cancer of glial cells (e.g., gliobiastoma multiforme) or cancer of the head and neck.
In one embodiment, the conjugate, particle or composition is administered in combination with one or more additional chemotherapeutic agents, for example, a chemotherapeutic agent (such as, an angiogenesis inhibitor) or combination of chemotherapeutic agents described herein. In one embodiment, the conjugate, particle or composition is administered in combination with one or more of: a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin), a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel) , a vinca alkaloid (eg, vinblastine, vincristine, viridinosin, vinorelbine), an antimetabolite (eg, an antifolate (eg, floxuridine, pemetrexed) and a pyrimidine analogue (eg, example, 5FU, capecitabine)), an alkylating agent (eg, cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide), an inhibitor of the vascular endothelial growth factor (VEGF) pathway, an inhibitor of poly ADP-ribose polymerase (PARP) and an mTOR inhibitor. In one embodiment, when the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP is administered in combination with an additional chemotherapeutic agent, the dose at which the conjugate, particle or composition of the bound topoisomerase inhibitor is administered CDP is 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30% lower than the doses described herein.
In one aspect, the disclosure presents a method for treating a proliferative disorder, eg, cancer, in a subject. The method includes: provide an initial administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a conjugate, particle or composition derived from camptothecin or camptothecin derivative linked to the CDP described herein, for example, CRLX101, to said subject in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2 (wherein said dosage is expressed in mg of the drug, as opposed to mg of the conjugate), optionally, providing one or more subsequent administrations of said conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or camptothecin composition or camptothecin derivative attached to the CDP, eg, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2, where each subsequent administration is provided, independently, between 5, 6, 7, 8, 9 days after the previous administration, by example, the initial administration, to treat thus the proliferative disorder.
In one embodiment, the dosage of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15 or 20 administrations is the same.
In one modality, the time between at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15 or 20 administrations is the same.
In one embodiment, each subsequent administration is administered 5-9, for example, 7 days after the previous administration. In one embodiment, 3 administrations are provided between 5, 6, 7, 8 or 9 days from the previous administration and the fourth administration is provided between 10, 11, 12, 13, 14, 15 or 16 days from the previous administration. The dosing schedule can be repeated with 3 additional administrations provided between 5, 6, 7, 8 or 9 days from the previous administration and the subsequent administration provided between 10, 11, 12, 13, 14, 15 or 16 days at from the previous administration.
In one embodiment, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 50 or 100 administrations are administered to said subject.
In one embodiment, the drug is provided at 9-33 mg / m2 /month.
In one embodiment, the conjugate includes a topoisomerase I inhibitor and / or a topoisomerase II inhibitor. In one embodiment, the conjugate includes a topoisomerase I inhibitor or combination of topoisomerase I inhibitors, for example, camptothecin, irinotecan, SN-38, topotecan, lamelarin D, and derivatives thereof. In one embodiment, the conjugate includes a topoisomerase II inhibitor or a combination of topoisomerase II inhibitors, e.g., eptoposide, tenoposide, doxoubicha, and derivatives thereof. In one embodiment, the conjugate includes a combination of one or more topoisomerase I inhibitors and one or more topoisomerase II inhibitors. In one embodiment, the conjugate of the topoisomerase inhibitor bound to the CDP is a camptothecin conjugate or camptothecin derivative linked to the CDP, eg, a camptothecin or camptothecin derivative linked to the CDP described herein, for example, CRLX101.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin or camptothecin derivative linked to the CDP, a camptothecin conjugate, particle or composition of camptothecin attached to the CDP described in present, for example, CRLX101, is administered by intravenous administration for a period equal to or less than about 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes or 180 minutes. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2, by intravenous administration for a period equal to or less than about 30 minutes, 45 minutes, 60 minutes or 90 minutes, for example, a period equal to or less than 30 minutes, 45 minutes or 60 minutes.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2, for example, with the same dosage as the initial dosage, wherein each subsequent administration is provided, independently 5-9, for example, 7 days after the previous administration, for example , the initial administration, and the cancer is, for example, lung cancer, for example, non-small cell lung cancer and / or small cell lung cancer (e.g., non-squamous cell lung cancer or small cell lung cancer). squamous cells). In one embodiment, lung cancer is insensitive, unruly or resistant to a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin) and / or a taxane (e.g., docetaxel, paclitaxel, larotaxel, cabazitaxel).
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2 Y one or more subsequent administrations of CRLX101 to said subject, in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2, for example, with the same dosage as the initial dosage, wherein each subsequent administration is provided, independently, 5-9, for example, 7 days after the previous administration, by example, the initial administration, and cancer is, for example, ovarian cancer. In one embodiment, ovarian cancer is insensitive, unruly or resistant to a platinum-based agent (eg, carboplatin, cisplatin, oxaliplatin). In one embodiment, CRLX101 is administered by intraperitoneal administration.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2 Y one or more subsequent administrations of CRLX101 to said subject, in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2, for example, with the same dosage as the initial dosage, wherein each subsequent administration is provided, independently, 5-9, for example, 7 days after the previous administration, by example, initial, and the cancer is, for example, gastric cancer, for example, gastroesophageal, upper gastric or lower gastric cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2 Y one or more subsequent administrations of CRLX101 to said subject, in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2, for example, with the same dosage as the initial dosage, wherein each subsequent administration is provided, independently, 5-9, for example, 7 days after the previous administration, by example, the initial administration, and cancer is, for example, pancreatic cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11; mg / m2 Y one or more subsequent administrations of CRLX101 to said subject, in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2, for example, with the same dosage as the initial dosage, wherein each subsequent administration is provided, independently, 5-9, for example, 7 days after the previous administration, by example, initial administration, and cancer is, for example, colorectal cancer.
In one embodiment, the method includes an initial administration of CRLX101 to said subject in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2 and one or more subsequent administrations of CRLX101 to said subject, in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 1 mg / m2, for example, with the same dosage as the initial dosage, wherein each subsequent administration is provided, independently, 5-9, for example, 7 days after the previous administration, by example, the initial administration, and the cancer is, for example, breast cancer, for example, estrogen receptor positive breast cancer, estrogen receptor negative breast cancer, HER-2 positive breast cancer, breast cancer HER-2 negative, triple negative breast cancer or inflammatory breast cancer.
In one embodiment, cancer is a cancer described herein. For example, the cancer can be a bladder cancer (including accelerated and metastatic bladder cancer), breast cancer (e.g., estrogen receptor positive breast cancer, estrogen receptor negative breast cancer, HER breast cancer). -2 positive, HER-2 negative breast cancer, triple negative breast cancer, inflammatory breast cancer), colon (including colorectal cancer), kidney, liver, lung cancer (including small cell lung cancer and lung cancer) non-small cell (including adenocarcinoma, squamous cell carcinoma, bronchioalveolar carcinoma, and large cell carcinoma)), genitourinary tract, eg, ovarian (including cancers of the fallopian, endometrium, and peritoneal), cervix, prostate, and testicles, lymphatic system , rectum, larynx, pancreas (including exocrine pancreatic carcinoma), stomach (for example, gastroesophageal, upper gastric, or lower gastric cancer), gastrointestinal cancer (eg, anal cancer), gallbladder, thyroid, lymphoma (eg, Burkitt's lymphoma, Hodgkin's or non-Hodgkin's lymphoma), leukemia (eg, acute myeloid leukemia), Ewing's sarcoma, nasoesophageal cancer, nasopharyngeal cancer , neuronal cancers and glial cells (eg, glioblastoma multiforme), and head and neck ^ Preferred cancers include breast cancer (eg, locally advanced or metastatic breast cancer), prostate cancer (e.g., hormone-refractory prostate cancer), renal cell carcinoma, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer (including adenocarcinoma, squamous cell carcinoma, bronchioalveolar carcinoma, and large cell carcinoma) )), pancreatic cancer, gastric cancer (eg, gastroesophageal, upper gastric or lower gastric cancer), colorectal cancer, squamous cell cancer of the head and neck, ovarian cancer (eg, advanced ovarian cancer, ovarian cancer) unruly or resistant to a platinum-based agent), lymphoma (e.g., Burkitt's lymphoma, Hodgkin's or non-Hodgkin's lymphoma), leukemia (e.g., acute myeloid leukemia) and gastrointestinal cancer.
In one embodiment, the cancer is ovarian cancer, colorectal, breast, lung, lymphoma or gastric cancer. In one embodiment, the cancer is a cancer other than pancreatic cancer, renal cell carcinoma and / or lung cancer (e.g., non-small cell lung cancer). In one embodiment, cancer is a cancer other than pancreatic cancer, renal cell carcinoma, lung cancer (e.g., non-small cell lung cancer) and / or ovarian cancer.
In one embodiment, the subject has not been administered a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, eg, CRLX101, prior to the initial administration.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to CDP is administered as a first-line treatment for cancer.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered as a second, third or fourth line treatment for cancer. In one embodiment, the cancer is responsive to one or more of the chemotherapeutic agents, for example, a platinum-based agent, a taxane, an alkylating agent, an antimetabolite and / or a vinca alkaloid. In one embodiment, the cancer is insensitive, unruly or resistant to one or more chemotherapeutic agents, for example, a platinum-based agent, a taxane, an alkylating agent, an anthracycline (eg, doxorubicin (eg, liposomal doxorubicin)) and an antimetabolite and / or a vinca alkaloid. In one embodiment, the cancer is, for example, ovarian cancer, and ovarian cancer is insensitive, unruly or resistant to a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin), a taxane (e.g., paclitaxel). , docetaxel, larotaxel, cabazitaxel) and / or an anthracycline (eg, doxorubicin (eg, liposomal doxorubicin)). In one embodiment, the cancer is, for example, colorectal cancer, and the cancer is insensitive, unruly or resistant to an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) and a pyrimidine analogue (e.g. , capecitabine, citrarabine, gemcitabine, 5FU)) and / or a platinum-based agent (eg, carboplatin, cisplatin, oxaliplatin). In one embodiment, the cancer is, for example, lung cancer, and the cancer is insensitive, unresponsive, or resistant to a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel), a platinum-based agent (e.g., carboplatin). , cisplatin, oxaliplatin), a vinca alkaloid (eg, vinblastine, vincristine, vindesine, vinorelbine), an inhibitor of the vascular endothelial growth factor (VEGF) pathway, an inhibitor of the epidermal growth factor pathway ( EGF) and / or an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) and a pyrimidine analogue (e.g., capecitabine, citrarabine, gemcitabine, 5FU)). In a modality, cancer is, for example, breast cancer, and the cancer is insensitive, unruly or resistant to a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel), an inhibitor of the vascular endothelial growth factor (VEGF) pathway ), an anthracycline (e.g., daunorubicin, doxorubicin (e.g., liposomal doxorubicin), epirubicin, valrubicin, idarubicin), a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin) and / or an antimetabolite (e.g. an antifolate (eg, pemetrexed, floxuridine, raltitrexed) and a pyrimidine analogue (eg, capecitabine, citrarabine, gemcitabine, 5FU)). In one embodiment, the cancer is, for example, gastric cancer, and the cancer is insensitive, unruly or resistant to an antimetabolite (e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) and a pyrimidine analogue (e.g. , capecitabine, citrarabine, gemcitabine, 5FU)) and / or a platinum-based agent (eg, carboplatin, cisplatin, oxaliplatin).
In one embodiment, the subject has ovarian cancer that is insensitive, unruly or resistant to a platinum-based agent, and the subject is administered a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a conjugate. , particle or composition of the topoisomerase inhibitor bound to the CDP described herein. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with doxorubicin (eg, liposomal doxorubicin). In one embodiment, doxorubicin (eg, liposomal doxorubicin) is administered at a dose of about 20 mg / m2, about 30 mg / m2 or about 40 mg / m2, every 24, 25, 26, 27, 28, 29, 30 or 31 days, for example, 28 days. In one embodiment, when the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with doxorubicin (eg, liposomal doxorubicin), the dose at which the conjugate, particle or composition of the inhibitor is administered. Topoisomerase attached to the CDP is 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30% lower than the dose described herein.
In one embodiment, the cancer has been sensitized to a topoisomerase inhibitor, e.g., the subject has received radiation and / or the subject has received a phosphatase inhibitor (e.g., okadaic acid) prior to administration of the conjugate, particle or topoisomerase inhibitor composition bound to the CDP. In one embodiment, the cancer is sensitized to topoisomerase inhibitors, for example, the subject receives radiation in combination with the administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP and / or the subject is administered an inhibitor. of the phosphatase (eg, okadaic acid) in combination with the administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP. In one embodiment, the cancer is sensitized or sensitized to topoisomerase inhibitors and the cancer is a cancer of glial cells (e.g., glioblastoma multiforme) or cancer of the head and neck.
In one embodiment, the conjugate, particle or composition is administered in combination with one or more additional chemotherapeutic agents, for example, a chemotherapeutic agent (such as, an angiogenesis inhibitor) or combination of chemotherapeutic agents described herein. In one embodiment, the composition is administered in combination with one or more of: a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin), a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel), an alkaloid of vinca (for example, vinblastine, vincristine, vindesine, vinorelbine), an antimetabolite (for example, an antifolate (for example, pemetrexed, floxuridine, raltitrexed) and a pyrimidine analog (for example, 5FU, capecitabine, citrarabine, gemcitabine) ), an alkylating agent (eg, cyclophosphamide, decarbazine, melphalan, phosphamide, temozolomide), an inhibitor of the vascular endothelial growth factor (VEGF) pathway, an inhibitor of poly ADP-ribose polymerase (PARP) and a mTOR inhibitor. In one embodiment, when the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with an additional chemotherapeutic agent, the dose at which the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP is administered. it is 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30% less than the dose described here.
In one embodiment, the method further comprises administering to said subject a treatment that reduces one or more side effects associated with the administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a treatment described herein. .
In one aspect, the description presents a method for treating ovarian cancer (e.g., epithelial carcinoma, cancer of the fallopian tube, germ cell cancer (eg, a teratoma), stromal tumor and sex cords (eg, tumor of granulosa cells that produce estrogen, Sertoli-Leydig virilizing tumor, arrenoblastoma)), for example, metastatic or locally advanced ovarian cancer, in a subject, for example, a human subject. The method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a conjugate, particle or camptothecin composition. or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in combination with a second chemotherapeutic agent.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor of the CDP bound, eg, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered before surgery, after surgery or before and after surgery to remove the cancer, for example, to remove a main tumor and / or a metastasis.
In one embodiment, the method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a conjugate, particle or Camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in combination with a platinum-based agent (eg, cisplatin, carboplatin, oxaliplatin). In one embodiment, the conjugate, particle or composition is further administered in combination with an antimetabolite, for example, an antifolate (eg, pemetrexed, floxuridine, raltitrexed) or pyrimidine analogue (eg, capecitabine, citrarabine, gemcltabin, 5FU) ). In one embodiment, the conjugate, particle or composition is further administered in combination with an antimetabolite, for example, an antifolate (eg, pemetrexed, floxuridine, raltitrexed) or pyrimidine analogue (eg, capecitabine, citrarabine, gemcitabine, 5FU) ) and folinic acid (leucovorin).
In one embodiment, the conjugate, particle or composition is administered in combination with an angiogenesis inhibitor (eg, an angiogenesis inhibitor described herein, such as an inhibitor of the VEGF pathway). In one embodiment, the method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a conjugate, particle or Camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in combination with a taxane (for example, paclitaxel, docetaxel, larotaxel, cabazitaxel). In one embodiment, the conjugate, particle or composition is further administered in combination with a platinum-based agent (e.g., cisplatin, carboplatin, oxaliplatin). In one embodiment, the conjugate, particle or composition is further administered in combination with an antimetabolite, for example, an antifolate (eg, pemetrexed, floxuridine, raltitrexed) or pyrimidine analogue (eg, capecitabine, citrarabine, gemcitabine, 5FU) ). In one embodiment, the conjugate, particle or composition is further administered in combination with an antimetabolite, for example, an antifolate (eg, pemetrexed, floxuridine, raltitrexed) or pyrimidine analogue (eg, capecitabine, citrarabine, gemcitabine, 5FU) ) and folinic acid (leucovorin).
In one embodiment, the method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a conjugate, particle or camptothecin or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in combination with an anthracycline (eg, doxorubicin (eg, liposomal doxorubicin), daunorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin). In one embodiment, the cancer is insensitive, unruly or resistant to a taxane and / or a platinum-based agent.
In one embodiment, the conjugate, particle or composition is administered in combination with one or more of: an antimetabolite, e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) or pyrimidine analogue (e.g., capecitabine, citrarabine, gemcitabine, 5FU); an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide); a platinum-based agent (carboplatin, cisplatin, oxaliplatin); a vinca alkaloid (for example, vinblastine, vincristine, vindesine, vinorelbine). In one embodiment, the conjugate, particle or composition is administered in combination with one or more of: capecitabine, cyclophosphamide, gemcitabine, ifosfamide, meifaltan, oxaliplatin, vinorelbine, vincristine and pemetrexed. In one embodiment, the cancer is insensitive, unruly or resistant to a taxane and / or a platinum-based agent.
In one embodiment, the conjugate, particle or composition is administered in a dose and / or dosage program described herein. In one embodiment, when the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with an additional chemotherapeutic agent, the dose at which the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP is administered. it is 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30% less than the dose described here.
In one embodiment, the conjugate, particle or composition is administered in combination with a treatment that reduces one or more side effects associated with the administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a treatment described at the moment.
In another aspect, the disclosure features a method for treating colorectal cancer (e.g., colon, small intestine, rectal and / or appendix cancer), e.g., metastatic or locally advanced cancer, in a subject, e.g., a subject human. The method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, in combination with a second chemotherapeutic agent.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, for example, a camptothecin conjugate, particle or composition. camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered before surgery, after surgery or before and after surgery to remove the cancer, for example, to remove the main tumor and / or a metastasis.
In one embodiment, the method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a conjugate, particle or Camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in combination with an antimetabolite, for example, an antifolate (eg, pemetrexed, floxuridine, raltitrexed). In one embodiment, the conjugate, particle or composition is administered in combination with an antimetabolite, for example, a pyrimidine analog (e.g., capecitabine, citrarabine, gemcitabine, 5FU)) and folinic acid (leucovorin). In one embodiment, the conjugate, particle or composition is additionally administered in combination with a platinum-based agent (e.g., cisplatin, carboplatin, oxaliplatin). For example, in one embodiment, the conjugate, particle or composition is administered in combination with an antimetabolite, for example, 5FU, folinic acid (leucovorin) and a platinum-based agent, for example, oxaliplatin. In another embodiment, the antimetabolite is a pyrimidine analog, for example, capecitabine.
In one embodiment, the conjugate, particle or composition is administered in combination with an angiogenesis inhibitor (eg, an angiogenesis inhibitor described in the present, such as an inhibitor of the VEGF pathway). In one embodiment, the method includes administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition of camptothecin linked to the CDP, eg, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in combination with a platinum-based agent (eg, cisplatin, carboplatin, oxaliplatin).
In one embodiment, the method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a conjugate, particle or camptothecin compound or camptothecin derivative linked to the CDP, eg, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in combination with an inhibitor of the vascular endothelial growth factor (VEGF) pathway, eg, a VEGF inhibitor or receptor inhibitor of VEGF. In one embodiment, the VEGF inhibitor is bevacizumab or AV-951. In one embodiment, the VEGF receptor inhibitor is selected from CP-547632 and AZD2171. In one embodiment, the conjugate, particle or composition is administered in combination with an inhibitor of the VEGF pathway, eg, bevacizumab and an antimetabolite, eg, an antifolate (eg, pemetrexed, floxuridine, raltitrexed) or pyrim analogue. idina (for example, capecitabine, 5FU, citrprabine, gemcitabine). In one embodiment, the conjugate, particle or composition is administered with an inhibitor of the VEGF pathway, for example, bevacizumab, an antimetabolite, for example, a pyrimidine analog (e.g., 5FU) and folinic acid (leucovorin). In another embodiment, the conjugate, particle or composition is administered with an inhibitor of the VEGF pathway, eg, bevacizumab, an antimetabolite, for example, a pyrimidine analog (e.g., 5FU), folinic acid (leucovorin) and a platinum-based agent (e.g., cisplatin, carboplatin, oxaliplatin). In one embodiment, the cancer is insensitive, unruly or resistant to an antimetabolite and / or a platinum-based agent.
In another embodiment, a conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP, for example, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP described herein, eg, CRLX101, is administered in combination with an inhibitor of the VEGF pathway, for example, bevacizumab, and an antimetabolite where the antimetabolite is a pyrimidine analog, for example, capecitabine. In one embodiment, the conjugate, particle or composition is further administered in combination with a platinum-based agent (e.g., cisplatin, carboplatin, oxaliplatin). For example, in one embodiment, the conjugate, particle or composition is administered with the following combination: an inhibitor of the VEGF pathway, eg, a VEGF inhibitor (eg, bevacizumab) or a VEGF receptor inhibitor, a pyrimidine analog (e.g., capecitabine) and a platinum-based agent (e.g., oxaliplatin); or an inhibitor of the VEGF pathway (eg, bevacizumab) and a pyrimidine analogue (eg, capecitabine). In one embodiment, the cancer is insensitive, unruly or resistant to an antimetabolite and / or a platinum-based agent.
In one embodiment, a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition or Camptothecin derivative linked to CDP described herein, for example, CRLX101, is administered in combination with an inhibitor of the epidermal growth factor (EGF) pathway, eg, an EGF inhibitor or EGF receptor inhibitor. The EGF receptor inhibitor can be, for example, cetuximab, erlotinib, gefitinib, panitumumab. In one embodiment, the conjugate, particle or composition is administered in combination with an inhibitor of the EGF pathway, for example, cetuximab or panitumumab and a VEGF pathway inhibitor, eg, bevacizumab. In one embodiment, the cancer is insensitive, unruly or resistant to an antimetabolite and / or a platinum-based agent.
In one embodiment, the conjugate, particle or composition is administered in a dose and / or dosage program described herein. In one embodiment, when the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with an additional chemotherapeutic agent, the dose at which the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP is administered. it is 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30% less than the dose described here.
In one embodiment, the conjugate, particle or composition is administered in combination with a treatment that reduces one or more side effects associated with the administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a treatment described at the moment.
In one aspect, the disclosure features a method for treating lung cancer (e.g., microcytic lung cancer or non-small cell lung cancer (e.g., adenocarcinoma, squamous cell carcinoma, bronchioalveolar carcinoma, and large cell carcinoma)), for example, locally advanced or metastatic cancer, in a subject, for example, a human subject. The method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a conjugate, particle or composition of the inhibitor of topoisomerase I or II linked to the CDP, for example, a conjugate, particle or composition of camptothecin or camptothecin derivative linked to CDP, for example, a camptothecin conjugate, particle or camptothecin composition or camptothecin derivative attached to the CDP described herein, for example, CRLX101. In one embodiment, the method comprises selecting a subject having squamous cell lung cancer for treatment with a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a conjugate, particle or composition of the inhibitor of the topoisomerase I or II linked to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, for example, a camptothecin conjugate, particle or camptothecin composition or camptothecin derivative attached to the CDP described herein, for example, CRLX101.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP, for example a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP described herein, eg, CRLX101, is administered prior to surgery, after surgery or before and after surgery to remove the cancer, for example, to remove a primary tumor and / or a metastasis.
In one embodiment, the method includes selecting a subject who has lung cancer and who has increased the levels of KRAS and / or ST expression, for example, compared to a reference standard and / or has a mutation in the gene KRA $ and / or ST and administer a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or camptothecin composition or camptothecin derivative bound to the CDP, eg, a conjugate, or camptothecin particle or camptothecin derivative linked to the CDP described herein, eg, CRLX101, to the subject in an amount effective to treat cancer, to thereby treat the cancer.
In one embodiment, the subject has increased levels of KRAS and / or ST expression, for example, compared to a reference standard, and / or has a mutation in the KRAS and / or ST gene. In one embodiment, the subject has a mutation in one or more of: codon 12 of the KRAS gene (eg, a transversion G to T), codon 13 of the KRAS gene, codon 61 of the KRAS gene. In one modality, the Subject has non-small cell lung cancer associated with mucinous bronchioloalveolar cells or Goblet cells.
In one embodiment, the method includes selecting a subject having lung cancer and having a mutation in an EGFR gene and administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a conjugate, particle or composition of camptothecin or camptothecin derivative linked to CDP, eg, a camptothecin conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, eg, CRLX101, to the subject in an amount effective to treat cancer, for treat cancer like that.
In one embodiment, the subject has lung cancer that is resistant, unruly or insensitive to an EGF pathway inhibitor, eg, an EGF receptor inhibitor (e.g., erlotinib).
In one embodiment, the subject has one or more of the following mutations: codon 719 of the EGFR gene (eg, a nonsense mutation that causes a substitution of glycine to cysteine, alanine or serine at codon 719 of the EGFR gene), codon 746 of the EGFR gene (e.g., deletion of one or more nucleic acids from codon 746 of the EGFR gene), codon 747 of the EGFR gene (e.g., deletion of one or more nucleic acids from codon 747 of the EGFR gene), codon 748 of the EGFR gene (eg, deletion of one or more nucleic acids from codon 748 of the EGFR gene), coding 749 of the EGFR gene (eg, deletion of one or more nucleic acids from codon 749 of the EGFR gene), codon 750 of the EGFR gene (e.g., removal of one or more nucleic acids from codon 750 of the EGFR gene), codon 858 of the EGFR gene (eg, a nonsense mutation that results in a substitution of leucine to arginine at codon 858 of the EGFR gene), a deletion in exon 19 of the EGFR gene and an insertion mutation in exon 20 of the EGFR gene.
In one embodiment, the subject has a mutation in the EGFR gene and has a mutation in the KRAS gene and / or KRAS overexpression, for example, compared to a reference standard.
In one embodiment, the method includes selecting a subject having lung cancer and not having a mutation in an EGFR gene and administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a conjugate, particle or camptothecin composition or camptothecin derivative linked to CDP, eg, a camptothecin conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, eg, CRLX101, to the subject in an amount effective to treat cancer, to treat cancer like that.
In one embodiment, the method includes selecting a subject having squamous cell cancer; Y administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a conjugate, particle or camptothecin composition or derivative of camptothecin bound to the CDP described herein, for example, CRLX101, to the subject in an amount effective to treat the cancer, to thereby treat the cancer.
In one embodiment, the subject does not have one or more of the following mutations: codon 719 of the EGFR gene (eg, a nonsense mutation that causes a substitution of glycine to cysteine, alanine or serine at codon 719 of the EGFR gene), codon 746 of the EGFR gene (e.g., deletion of one or more nucleic acids from codon 746 of the EGFR gene), codon 747 of the EGFR gene (e.g., deletion of one or more nucleic acids from codon 747 of the EGFR gene), codon 748 of the EGFR gene (e.g., deletion of one or more nucleic acids from codon 748 of the EGFR gene), codon 749 of the EGFR gene (e.g., deletion of one or more nucleic acids from codon 749 of the EGFR gene), codon 750 of the EGFR gene (e.g., deletion of one p plus nucleic acids from codon 750 of the EGFR gene), codon 858 of the EGFR gene (e.g., a nonsense mutation that results in a substitution of leucine to arginine at codon 858 of the EGFR gene), a deletion in the exon 19 of the EGFR gene and an insertion mutation in exon 20 of the EGFR gene.
In one embodiment, the subject has a mutation in the gene KRAS and / or KRAS overexpresses, for example, compared to a reference standard, and does not have a mutation in the EGFR gene.
In one embodiment, the subject is insensitive, unruly or resistant to one or more chemotherapeutic agents, for example, a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin) and / or an EGF pathway inhibitor, e.g. , an EGF inhibitor or an EGFR inhibitor, for example, erlotinib.
In one embodiment, the conjugate, particle or composition is administered in a dose and / or dosage program described herein.
In one embodiment, the conjugate, particle or composition is administered in combination with a treatment that reduces one or more side effects associated with the administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a treatment described at the moment.
In one aspect, the disclosure presents a method for treating lung cancer (e.g., small cell lung cancer and non-small cell lung cancer (e.g., adenocarcinoma, squamous cell carcinoma, bronchioalveolar carcinoma, and large cell carcinoma)), for example, metastatic or locally advanced cancer, in a subject, for example, a human subject. The method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a conjugate, particle or composition of the inhibitor of topoisomerase I or II linked to the CDP, for example, a conjugate, particle or composition of camptothecin or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in combination with a second eutomeric agent In one embodiment, the method includes selecting a subject that has squamous cell cancer; Y administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition of camptothecin attached to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, to the subject in an amount effective to treat the cancer, to thereby treat the cancer.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered before surgery, after surgery or before and after surgery to remove the cancer, for example, to remove a primary tumor and / or a metastasis.
In one embodiment, the method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in combination with an inhibitor of the epidermal growth factor (EGF) pathway, eg, an EGF inhibitor or EGF receptor inhibitor . The EGF receptor inhibitor can be, for example, cetuximab, erlotinib, gefitinib, panitumumab. In one embodiment, the subject has a mutation in codon 858 of the gene encoding the EGF receptor, for example, which causes a substitution of a leucine to an arginine in the EGF receptor. In one embodiment, the conjugate, particle or composition is administered in combination with an inhibitor of the EGF pathway, eg, cetuximab, erlotinib, gefitinib, panitumumab and radiation. In one embodiment, the conjugate, particle or composition is administered in combination with an inhibitor of the EGF pathway, for example, cetuximab, erlotinib, gefitinib, panitumumab and one or more additional chemotherapeutic agents. For example, the chemotherapeutic agent can be a platinum-based agent (e.g., carboplatin, oxaliplatin), a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel), a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine), an antimetabolite, for example, an antifolate (eg, pemetrexed, floxuridine, raltitrexed) or pyrimidine analogue (eg, capecitabine, citrarabine, gemcitabine, 5FU) and combinations thereof.
In one embodiment, a conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, for example, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to CDP described herein, for example, CRLX101, is administered in combination with an inhibitor of the vascular endothelial growth factor (VEGF) pathway, for example, a VEGF inhibitor or VEGF receptor inhibitor. In one embodiment, the VEGF inhibitor is bevacizumab or AV-951. In one embodiment, the VEGF receptor inhibitor is selected from CP-547632 and AZD2171. In one embodiment, the conjugate, particle or composition is administered in combination with an inhibitor of the VEGF pathway, eg, bevacizumab and radiation. In one embodiment, the conjugate, particle or composition is administered in combination with an inhibitor of the VEGF pathway, eg, bevacizumab and one or more additional chemotherapeutic agents. For example, the chemotherapeutic agent may be a platinum-based agent (e.g., carboplatin, oxaliplatin), a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel), a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine), an antimetabolite, for example, an antifolate (eg, pemetrexed, floxuridine, raltitrexed) or pyrimidine analogue (eg, capecitabine, citrarabine, gemcitabine, 5FU) and combinations thereof. In one embodiment, the cancer is insensitive, unruly or resistant to one or more therapeutic agents, for example, an inhibitor of the EGF pathway, for example, erlotinib.
In one embodiment, the conjugate, particle or composition is administered in combination with an angiogenesis inhibitor (eg, an angiogenesis inhibitor described herein, such as an inhibitor of the VEGF pathway). In one embodiment, a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a conjugate, particle or camptothecin composition. or camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with a platinum-based agent (eg, cisplatin, carboplatin, oxaliplatin). For example, the conjugate, particle or composition is further administered in combination with a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel), a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine) and / or an antimetabolite, e.g., an antifolate (e.g., pemetrexed, floxuridine, raltitrexed) or pyrimidine analogue (e.g., capecitabine, citrarabine, gemcitabine, 5FU). In one embodiment, the method further includes administering radiation to the subject. In one embodiment, the cancer is insensitive, unruly or resistant to one or more therapeutic agents, for example, an inhibitor of the EGF pathway (eg, erlotinib), an inhibitor of the VEGF pathway and / or a taxane.
In one embodiment, a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition or Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel). In one embodiment, the method further includes administering radiation to the subject. In one embodiment, the cancer is insensitive, unruly or resistant to one or more therapeutic agents, eg, an EGF pathway inhibitor (eg, erlotinib), an inhibitor of the VEGF pathway and / or an agent based on platinum.
In a modality, a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP described herein, for example, CRLX101, is administered in combination with an antimetabolite, for example, an antifolate (eg, pemetrexed, floxuridine, raltitrexed). In one embodiment, the method further includes administering radiation to the subject. In one embodiment, the cancer is insensitive, unruly or resistant to one or more therapeutic agents, for example, an EGF pathway inhibitor (eg, erlotinib), an inhibitor of the VEGF pathway, a taxane and / or a platinum-based agent.
In one embodiment, the conjugate, particle or composition is administered in a dose and / or dosage schedule described herein. In one embodiment, when the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with an additional chemotherapeutic agent, the dose at which the conjugate, particle or composition of the topoisomerase inhibitor bound to CDP is administered is 1%, 3%, 5%, 10%, 15%, 20%, %, 30% lower than the dose described here.
In one embodiment, the conjugate, particle or composition is administered in combination with a treatment that reduces one or more side effects associated with the administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a treatment described at the moment.
In one aspect, the disclosure presents a method for treating breast cancer (e.g., estrogen receptor positive breast cancer, estrogen receptor negative breast cancer, HER-2 positive breast cancer, HER breast cancer). 2 negative, progesterone receptor breast cancer, negative progesterone receptor breast cancer, negative HER-2 and negative estrogen receptor (ie, triple negative breast cancer)), eg, metastatic breast cancer or locálmente advanced, in a subject, for example, a human subject. The method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a conjugate, particle or composition of the topoisomerase I or II inhibitor, eg, a conjugate, particle or camptothecin composition or derivative. of camptothecin bound to CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, in combination with a second chemotherapeutic agent.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered before surgery, after surgery or before and after surgery to remove the cancer, for example, to remove a primary tumor and / or a metastasis.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with an inhibitor of the HER-2 factor pathway, eg, a HER-2 inhibitor or a HER-2 receptor inhibitor. 2. For example, the conjugate, particle or composition of the topoisomerase inhibitor bound to CDP is administered with trastuzumab.
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition or Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with an inhibitor of the vascular endothelial growth factor (VEGF) pathway, eg, a VEGF inhibitor (eg, bevacizumab) or VEGF receptor inhibitor (e.g., CP-547632 and AZD2171). In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with bevacizumab. In some embodiments, the method further comprises administering a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel). In one embodiment, the method further comprises administering an inhibitor of the poly ADP-ribose polymerase (PARP) (eg, BSI 201, Olaparib (AZD-2281), ABT-888, AG014699, CEP 9722, MK 4827, KU -0059436 (AZD2281), LT-673, 3-aminobenzamide).
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with a platinum-based agent (eg, cisplatin, carboplatin, oxaliplatin). In some embodiments, the method further comprises administration of a taxane (e.g., paclitaxel, docetaxel, larotaxel, cabazitaxel). In some embodiments, the method further comprises administering a mTOR inhibitor. Non-limiting examples of mTOR inhibitors include rapamycin, everolimus, AP23573, CCI-779 and SDZ-RAD. In one embodiment, the method further comprises administering a PARP inhibitor (e.g., BSI 201, Olaparib (AZD-2281), ABT-888, AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281), LT- 673, 3-aminobenzamide). In some embodiments, the method further comprises administering a VEGF pathway inhibitor, e.g., a VEGF inhibitor (e.g., bevacizumab) or VEGF receptor inhibitor (e.g., CP-547632 and AZD2171).
In one embodiment, the conjugate, particle or composition is administered in combination with an angiogenesis inhibitor (eg, an angiogenesis inhibitor described herein, such as an inhibitor of the VEGF pathway). In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with a taxane (eg, docetaxel, larotaxel, cabazitaxel). In some embodiments, the method further comprises administering an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include rapamycin, everolimus, AP23573, CCI-779 and SDZ-RAD. In one embodiment, the method further comprises administering a PARP inhibitor (eg, BSI 201, Olaparib (AZD-2281), ABT-888, AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281), LT-673, 3-aminobenzamide).
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative uhida to the CDP described herein, for example, CRLX101, is administered in combination with an epothilone (for example, ixabelipone, epothilone B, epothilone D, BMS310705, dehydelone, ZK-EPO). In some embodiments, the method further comprises administering an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include rapamycin, everolimus, AP23573, CCI-779 and SDZ-RAD. In one embodiment, the method further comprises administering a PARP inhibitor (e.g., BSI 201, Olaparib (AZD-2281), ABT-888, AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281), LT- 673, 3-aminobenzamide). In some embodiments, the method further comprises administering a VEGF pathway inhibitor, e.g., a VEGF inhibitor (e.g., bevacizumab) or VEGF receptor inhibitor (e.g., CP-547632 and AZD2171). In some embodiments, the method further includes the administration of one or more of an anthracycline (e.g., daunorubicin, doxorubicin (liposomal doxorubicin), epirubicin, valrubicin, and idarubicin) and / or an antimetabolite (e.g., floxuridine, pemetrexed, 5FU) .
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with an anthracycline (eg, daunorubicin, doxorubicin (liposomal doxorubicin), epirubicin, valrubicin and idarubicin). In one embodiment, the cancer is insensitive, unruly or resistant to one or more therapeutic agents, for example, an HER-2 pathway inhibitor, a VEGF pathway inhibitor, a taxane, an antimetabolite and / or an agent based on platinum.
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with an antimetabolite, for example, an antifolate (eg, floxuridine, pemetrexed) or pyrimidine analogue (eg, 5GU)). In one embodiment, the cancer is insensitive, unruly or resistant to one or more therapeutic agents, for example, a inhibitor of the HER-2 pathway, an inhibitor of the VEGF pathway, a taxane, an anthracycline and / or a platinum-based agent.
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with an anthracycline (eg, daunorubicin, doxorubicin (liposomal doxorubicin), epirubicin, valrubicin and idarubicin) and an antimetabolite (eg, floxuridine, pemetrexed, 5FU). In one embodiment, the cancer is insensitive, unruly or resistant to one or more therapeutic agents, for example, an inhibitor of the HER-2 pathway, a VEGF pathway inhibitor and / or a platinum-based agent.
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include rapamycin, everolimus, AP23573, CCI-779 and SDZ-RAD. In some embodiments, the method further comprises administering a PARP inhibitor (e.g., BSI 201, Olaparib (AZD-2281), ABT-888, AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281), LT- 673, 3-aminobenzamide).
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with a PART inhibitor (eg, Olaparib (AZD-2281), ABT-888, AG014699, CEP 9722, MK 4827, KU- 0059436 (AZD2281), LT-673, 3-aminobenzamide).
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with a pyrimidine analog, for example, a pyrimidine analog described herein (eg, capecitabine). In some embodiments, the method further comprises administration of a taxane (e.g., dooetaxel, paclitaxel, larotaxel, cabazitaxel). In some embodiments, the method further comprises administering an epothilone (e.g., ixabelipone, epothilone B, epothilone D, BMS310705, dehydelone, ZK-EPO).
In one embodiment, the conjugate, particle or composition is administered in a dose and / or dosage program described herein. In one embodiment, when the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with an additional chemotherapeutic agent, the dose at which the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP is administered. it is 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30% less than the dose described here.
In one embodiment, the conjugate, particle or composition is administered in combination with a treatment that reduces one or more side effects associated with the administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a treatment described at the moment.
In one aspect, the disclosure presents a method for treating gastric cancer (eg, gastric (eg, intestinal or diffuse) adenocarcinoma, gastric lymphoma (eg, MALT lymphoma), carcinoid stromal tumor), eg, metastatic gastric cancer or locally advanced, in a subject, for example, a human subject. The method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a conjugate, particle or composition of the inhibitor of topoisomerase I or II linked to the CDP, for example, a conjugate, particle or composition of camptothecin or camptothecin derivative linked to CDP, eg, a camptothecin conjugate, particle or camptothecin composition or camptothecin derivative linked to CDP described herein, eg, CRLX101, in combination with a second chemotherapeutic agent.
In one modality, gastric cancer is adenocarcinomy of the gastroesophageal junction.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered before surgery, after surgery or before and after surgery to remove the cancer, for example, to remove a primary tumor and / or a metastasis.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition of camptothecin linked to the CDP, eg, a conjugate, particle, or composition of camptothecin or camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with one or more anthracyclines (eg, daunorubicin, doxorubicin (eg, liposomal doxorubicin), epirubicin, valrubicin, mitoxantrone and idarubicin ), a platinum-based agent (e.g., cisplatin, carboplatin, oxaloplatin) and an antimetabolite, e.g., an antifolate (e.g., floxuridine, pemetrexed, raltitrexed) or pyrimidine analogue (e.g., 5FU, capecitabine, citrarabine, gemcitabine)). For example, in one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a conjugate, particle or camptothecin composition or carnitothecin derivative attached to the CDP, eg, a conjugate, particle or composition of camptothecin or camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with an anthracycline (eg, daunorubicin, doxorubicin (eg, liposomal doxorubicin), epirubicin, valrubicin, mitoxantrone and idarubicin), a platinum-based agent (e.g., cisplatin, carboplatin, oxaliplatin) and an antimetabolite, e.g., an antifolate (e.g., floxuridine, pemetrexed, raltitrexed) or pyrimidine analog (e.g., 5FU, capecitabine, citrarabine, gemcitabine) . In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, for example, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with an anthracycline (eg, daunorubicin, doxorubicin (eg, liposomal doxorubicin), epirubicin, valrubicin, mitoxantrone and idarubicin). In one embodiment, the cancer is insensitive, unruly or resistant to one or more chemotherapeutic agents, for example, a platinum-based agent (eg, cisplatin, carboplatin, oxaliplatin).
In another embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, for example, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with a platinum-based agent (eg, cisplatin, carboplatin, oxaliplatin) and an antimetabolite, eg, an antifolate (eg, floxuridine) , pemetrexed, raltitrexed) or pyrimidine analog (for example, 5FU, capecitabine, citrarabine, gemcitabine).
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with an antimetabolite, for example, an antifolate (eg, floxuridine, pemetrexed, raltitrexed) or pyrimidine analogue (eg, capecitabine, 5FU , cytarabine, gemcitabine). In one embodiment, the method further comprises administering a taxane (e.g., paclitaxel, docetaxel, larotaxel, ca bazitaxel). For example, in a modality, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or camptothecin composition or camptothecin derivative attached to the CDP, for example, a camptothecin conjugate, particle or camptothecin composition or camptothecin derivative attached to the CDP described in present, for example, CRLX101, is administered in combination with an antimetabolite, for example, an antifolate (eg, floxuridine, pemetrexed, raltitrexed) or pyrimidine analogue (eg, capecitabine, 5FU, cytarabine, gemcitabine) and a taxane ( for example, paclitaxel, docetaxel, larotaxel, cabazitaxel).
In one embodiment, the conjugate, particle or composition is administered in combination with an angiogenesis inhibitor (eg, an angiogenesis inhibitor described herein such as an inhibitor of the VEGF pathway).
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with radiation.
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with an inhibitor of the vascular endothelial growth factor (VEGF) pathway, eg, a VEGF inhibitor (eg, bevacizumab) or VEGF receptor inhibitor (e.g., CP-547632 and AZD2171). In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative linked to the CDP described herein, for example, CRLX101, is administered in combination with bevacizumab. In one embodiment, the cancer is insensitive, unruly or resistant to one or more therapeutic agents, for example, an antimetabolite, a platinum-based agent and / or an anthracycline.
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, for example, a camptothecin conjugate, particle or camptothecin derivative or CDT-linked derivative described herein, for example, CRLX101, is administered in combination with an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include rapamycin, everolimus, AP23573, CCI-779 and SDZ-RAD. In one embodiment, the cancer is insensitive, unruly or resistant to one or more therapeutic agents, for example, an antimetabolite, a platinum-based agent and / or an anthracycline.
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a camptothecin conjugate, particle or composition. Camptothecin derivative bound to the CDP described herein, for example, CRLX101, is administered in combination with an inhibitor of poly ADP-ribose polymerase (PARP) (eg, Olaparib (AZD-2281), ABT-888, AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281), LT-673, 3-aminobenzamide). In one embodiment, the cancer is insensitive, unruly or resistant to one or more therapeutic agents, for example, an antimetabolite, a platinum-based agent and / or an anthracycline.
In one embodiment, the conjugate, particle or composition is administered in a dose and / or dosage program described herein. In one embodiment, when the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with an additional chemotherapeutic agent, the dose at which the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP is administered. it is 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30% less than the dose described here.
In one embodiment, the conjugate, particle or composition is administered in combination with a treatment that reduces one or more side effects associated with the administration of a conjugate, particle or composition of the topoisomerase inhibitor uhido to CDP, eg, a treatment described at the moment.
In one aspect, the invention features a method for treating pancreatic cancer in a subject, said method comprising administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP to the subject in combination with a pyrimidine analogue (by example, capecitabine, 5FU, citrarabine, gemcitabine). In one embodiment, the pyrimidine analog is gemcitabine.
In one aspect, the invention features a method of treating a proliferative disorder, eg, cancer, in a subject, for example, a human subject. The method includes: provide a subject having a proliferative disorder, for example, cancer and administering a composition comprising a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a conjugate, particle or composition of the inhibitor of topoisomerase I or II bound to the CDP, eg, a conjugate, particle or composition of camptothecin or camptothecin derivative linked to CDP, for example, a conjugate, particle or camptothecin-derivative composition bound to the CDP described herein, eg, CRLX101, to said subject in combination with an angiogenesis inhibitor.
In one modality, cancer is kidney cancer.
In one embodiment, the conjugate, particle or composition is administered in combination with an angiogenesis inhibitor described herein such as a VEGF pathway inhibitor (eg, an inhibitor of the VEGF pathway described herein). Examples of angiogenesis inhibitors include the following: A6 (Angstrom Pharmacueticals), ABT-510 (Abbott Laboratories), ABT-627 (Atrasentan) (Abbott Laboratories / Xinlay), ABT-869 (Abbott Laboratories), Actimid (CC4047, Pomalidomide ) (Celgene Corporation), AdGVPEDF.11 D (GenVec), ADH-1 (Exherin) (Adherex Technologies), AEE788 (Novartis), AG-013736 (Axitinib) (Pfizer), AG3340 (Prinomastat) (Agouron Pharmaceuticals), AGX1053 (AngioGenex), AGX51 (AngioGenex), ALN-VSP (ALN-VSP 02) (Alnylam Pharmaceuticals), AMG 386 (Amgen), AMG706 (Amgen), Apatinib (YN968D1) (Jiangsu Hengrui Medicine), AP23573 (Ridaforolimus / MK8669) (Ariadn Pharmaceuticals), AQ4N (Novavea), ARQ 197 (ArQule), ASA404 (Novartis / Antisoma), Atiprimod (Callisto Pharmaceuticals), ATN-161 (Attenuon), AV-412 (Aveo Pharmaceuticals), AV-951 (Aveo Pharmaceuticals ), Avastin (Bevacizumab) (Genentech), AZD2171 (Cediranib / Recentin) (AstraZeneca), BAY 57-9352 (Telatinib) (Bayer), BEZ235 (Novartis), BIBF1120 (Boehringer Ingelheim Pharmaceuticals), BIBW 2992 (Boehringer Ingelheim Pharmaceuticals), BMS-275291 (Bristol-Myers Squibb), BMS-582664 (Brivanib) (Bristol) -Myers Squibb), BMS-690514 (Bristol-Myers Squibb), Calcitriol, CCI-779 (Torisel) (Wyeth), CDP-791 (ImClone Systems), Ceflatonin (Homoharringtonine / HHT) (ChemGenex Therapeutics), Celebrex (Celecoxib) (Pfizer), CEP-7055 (Cephalon / Sanofi), CHIR-265 (Chiron Corporation), NGR-TNF, COL-3 (Metastat) (Collagenex Pharaceuticals), Combretastatin (Oxigene), CP-751,871 (Figitumumab) (Pfizer) , CP-547,632 (Pfizer), CS-7017 (Daiichi Sankyo Pharma), CT-322 (Angiocept) (Adnexus), Curcumin, Dalteparin (Fragmin) (Pfizer), Disulfiram (Antabuse), E7820 (Eisai Limited), E7080 ( Eisai Limited), EMD 12 974 (Cilengitide) (EMD Pharmaceuticals), ENMD-1198 (EntreMed), ENMD-2076 (EntreMed), Endostar (Simcere), Erbitux (ImClone / Bristol-Myers Squibb), EZN-2208 (Enzon Pharmaceuticals ), EZN-2968 (Enzon Ph armaceuticals), GC1008 (Genzyme), Genistein, GSK1363089 (Foretinib) (GlaxoSmithKine), GW786034 (Pazopanib) (GlaxoSmithKine), GT-111 (Vascular Biogenics Ltd.), IMC-1121B (Ramucirumab) (ImClone Systems), IMC- 18F1 (ImClone Systems), IMC-3G3 (ImClone LLC), INCB007839 (Incyte Corporation), INGN 241 (Introgen Therape tics), Iressa (ZD1839 / Gefitinib), LBH589 (Faridak / Panobinostst) (Novartis), Lucentis (Ranibizumab) ( Genentech / Novartis), LY317615 (Enzastaurin) (Eli Lilly and Company), Macugen (Pegaptanib) (Pfizer), MEDI522 (Abegrin) (Medlmmune), MLN518 (Tandut¡nib) (Millennium), Neovastat (AE941 / Benefin) (Aeterna Zentaris), Nexavar (Bayer / Onyx), NM-3 (Genzyme Corporation), Noscapine (Cougar Biotechnology), NPI-2358 (Nereus Pharmaceuticals), OSI-930 (OSI), Palomid 529 (Paloma Pharmaceuticals, Inc.), Panzem Capsules (2ME2) (EntreMed), Panzem NCD (2ME2) (EntreMed), PF-02341066 (Pfizer), PF-04554878 (Pfizer), PI-88 (Progen Industries / Medigen Biotechnology), PKC412 (Novartis), Polyphenon E ( Gre in Tea Extract) (Polyphene E International, Inc.), PPI-2458 (Praecis Pharmaceuticals), PTC299 (PTC Therapeutics), PTK787 (Vatalanib) (Novartis), PXD101 (Belinostat) (CuraGen Corporation), RAD001 (Everolimus) (Novartis) , RAF265 (Novartis), Regorafenib (BAY73-4506) (Bayer), Revlimid (Celgene), Retaane (Alcon Research), SN38 (üposomal) (Neopharm), SNS-032 (BMS-387032) (Sunesis), SOM230 (Pasireotide) ) (Novartis), Squalamine (Genaera), Suramin, Sutent (Pfizer), Tarceva (Genentech), TB-403 (Thrombogenics), Tempostatin (Collard Biopharmaceuticals), Tetrath iomoly bdate (Sigma-Aldrich), TG100801 (TargeGen), Thalidomide (Celgene Corporation), Tinzaparin Sodium, TKI258 (Novartis), TRC093 (Tracon Pharmaceuticals Inc.), VEGF Trap (Aflibercept) (Regeneron Pharmaceuticals), VEGF Trap-Eye (Regeneron Pharmaceuticals), Veglin (VasGene Therapeutics), Bortezomib (Millennium) , XL184 (Exelixis), XL647 (Exelixis), XL784 (Exelixis), XL820 (Exelixis), XL999 (Exelixis), ZD6474 (AstraZeneca), Vorinostat (Merck) and ZSTK474.
In one embodiment, the conjugate, particle or composition is administered in combination with a treatment that reduces one or more side effects associated with the administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a treatment described at the moment.
In one aspect, the disclosure presents a method for treating a prolifera disorder, eg, cancer, in a subject, e.g., a human subject. The method includes: providing a subject having a prolifera disorder, for example, cancer; administer a polysaccharide to said subject and administering a composition comprising a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a conjugate, particle or composition of the inhibitor of topoisomerase I or II bound to the CDP, eg, a conjugate, particle or composition of camptothecin or camptothecin deriva linked to the CDP, for example, a conjugate, particle or camptothecin-derived composition linked to the CDP described herein, eg, CRLX101, to said subject.
In one embodiment, the polysaccharide is a linear, branched or cyclic polysaccharide. In one embodiment, the polysaccharide is a linear polysaccharide that includes glucose molecules. In one embodiment, the polysaccharide is dextran, a cyclodextrin or a cyclodextrin deriva, for example, an α, β and / or β cyclodextrin, eg, CDP.
In one embodiment, the polysaccharide is administered before, together with or after administration of the composition. In a modality, the polysaccharide is administered in a dose of 100 mg to 10 g.
In one embodiment, the conjugate includes an inhibitor of topoisomerase I and / or a topoisomerase II inhibitor. In one embodiment, the conjugate includes a topoisomerase I inhibitor or combination of topoisomerase I inhibitors, for example, camptothecin, irinotecan, SN-38, topotecan, lamelarin D, and derivas thereof. In one embodiment, the conjugate includes a topoisomerase II inhibitor or a combination of topoisomerase II inhibitors, eg, eptoposide, tenoposide, doxorubicin, and derivas thereof. In one embodiment, the conjugate includes a combination of one or more inhibitors of topoisomerase I and one or more inhibitors of topoisomerase II. In one embodiment, the conjugate of the topoisomerase inhibitor bound to the CDPs is a camptothecin conjugate or camptothecin deriva linked to the CDP, for example, a camptothecin conjugate or camptothecin deriva linked to the CDP described herein, for example, CRLX101.
In one embodiment, the prolifera disorder is cancer, for example, a cancer described herein.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with one or more chemotherapeutic agents, for example, as described herein. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in a dose and / or schedule of dosage described herein. In one embodiment, the subject is administered more than one dose of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, as described herein, and the polysaccharide is administered before, together with or after one or more doses of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP.
In one aspect, the disclosure presents a method for treating a prolifera disorder, eg, cancer, in a subject, e.g., a human subject. The method includes: providing a subject having a prolifera disorder, for example, cancer; administering an agent that improves bladder toxicity associated with therapy, for example, an agent that increases urinary excretion and / or neutralizes one or more urinary metabolites and administer a composition comprising a camptothecin or camptothecin deriva, for example, a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or camptothecin composition or camptothecin deriva linked to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin deriva attached to the CDP described herein, for example, CRLX101, to said subject.
In one embodiment, the agent that improves bladder toxicity associated with therapy, for example, the agent that increases urinary excretion and / or neutralizes one or more urinary metabolites, is administered before, together with and / or after the administration with camptothecin or camptothecin derivative.
In one embodiment, the agent that improves bladder toxicity associated with therapy is saline, eg, intravenous saline, normal medium saline D5 or water Q5. In one embodiment, the agent that increases urinary excretion and / or neutralizes one or more urinary metabolites is sodium 2-mercaptoethane sulfonate (MESNA). In one embodiment, the agent that improves the toxicity of the bladder associated with the therapy is sodium 2-mercaptoethane sulfonate (MESNA) and MESNA is administered intravenously at a dose of about 10%, 20%, 30% of the dose of camptothecin or camptothecin derivative and / or MESNA is administered orally in a dose of about 20%, 30%, 40%, 50% of the camptothecin dose or camptothecin derivative.
In one embodiment, the conjugate includes an inhibitor of topoisomerase I and / or an inhibitor of topoisomerase II. In one embodiment, the conjugate includes a topoisomerase I inhibitor or combination of topoisomerase I inhibitors, for example, camptothecin, irinotecan, SN-38, topotecan, lamelarin D, and derivatives thereof. In one embodiment, the conjugate includes a topoisomerase II inhibitor or a combination of topoisomerase II inhibitors, eg, eptoposide, tenoposide, doxorubicin, and derivatives thereof. In one embodiment, the conjugate includes a combination of one or more inhibitors of topoisomerase I and one or more inhibitors of topoisomerase II. In one mode, the conjugate of the topoisomerase inhibitor bound to the CDP is a camptothecin conjugate or camptothecin derivative linked to the CDP, for example, a camptothecin conjugate or camptothecin derivative linked to the CDP described herein, for example, CRLX101 .
In one embodiment, the proliferative disorder is cancer, for example, a cancer described herein.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP described herein, eg, a conjugate, particle or composition of camptothecin or camptothecin derivative linked to CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP described herein, is administered in combination with one or more chemotherapeutic agents, for example, as describes in the present. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in a dose and / or dosage program described herein. In one embodiment, the subject is administered more than one dose of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, as described herein, and the agent that enhances the toxicity of the associated bladder. with the therapy is administered before one or more doses of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is further administered in combination with one or more of the agents described herein. For example, the conjugate, particle or composition of the topoisomerase inhibitor bound to CDP can be administered in combination with an agent that reduces or inhibits one or more symptoms of hypersensitivity.
In one embodiment, the method includes selecting a subject that has a proliferative disorder, eg, cancer, and has experienced cystitis, for example, has experienced cystitis as a result of prior chemotherapeutic treatment, for the administration of an agent that improves toxicity of the bladder associated with the therapy and a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative attached to the CDP, eg, a conjugate, particle or Camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101.
In one aspect, the disclosure presents a method for treating a proliferative disorder, eg, a cancer, in a subject, e.g., a human subject. The method includes: providing a subject having a proliferative disorder, eg, cancer, and having been administered an agent that reduces or inhibits one or more symptoms of hypersensitivity; Y administering a composition comprising a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or camptothecin derivative or camptothecin derivative attached to the CDP, eg, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, eg, CRLX101, to said subject.
In one embodiment, the method further comprises administering the agent that reduces or inhibits one or more symptoms of hypersensitivity to the subject.
In one embodiment, the agent that reduces or inhibits one or more hypersensitivity symptoms may be one or more of a corticosteroid (e.g., dexamethasone), an antihistaminic (e.g., diphenhydramine), an H1 antagonist and an H2 antagonist (e.g. , ranitidine or famotidine). In one embodiment, the agent is a corticosteroid (e.g., dexamethasone) and the corticosteroid is administered at 5, 10, 15, 20, 25 or 30 mg. In one embodiment, the corticosteroid is administered at about 12, 11, 10, 9, 8, 7, 6, 5, 4 and / or 3 hours before the administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP. , or the corticosteroid is administered intravenously about 40, 30, 20 minutes before the conjugate, particle or composition of the inhibitor of topoisomerase attached to CDP. In one embodiment, the agent is an antihistamine (e.g., diphenhydramine) and the antihistamine is administered at 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 or 70 mg. In one embodiment, the antihistamine is administered intravenously about 40, 30, 20, 10 minutes before the conjugate, particle or composition of the topoisomeric inhibitor bound to the CDP. In one embodiment, the agent is an H2 antagonist (eg, ranitidine or famotidine) and the H2 antagonist is administered at 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 or 70 mg. In one embodiment, the H2 antagonist is administered intravenously at about 70, 60, 50, 40, 30, 20, 10 minutes before the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP.
In one embodiment, the conjugate includes an inhibitor of topoisomerase I and / or an inhibitor of topoisomerase II. In one embodiment, the conjugate includes an inhibitor of topoisomerase I or combination of inhibitors of topoisomerase I, for example, camptothecin, irinotecan, SN-38, topotecan, lamelarin D and dlerivatives thereof. In one embodiment, the conjugate includes a Topoisomerase II Inhibitor or a combination of topoisomerase II inhibitors, for example, eptoposide, tenoposide, doxorubicin, and derivatives thereof. In one embodiment, the conjugate includes a combination of one or more inhibitors of topoisomerase I and one or more inhibitors of topoisomerase II. In one embodiment, the conjugate of the topoisomerase inhibitor bound to the CDP is a Camptothecin conjugate or camptothecin derivative linked to the CDP, for example, a camptothecin conjugate or camptothecin derivative linked to the CDP described herein, for example, CRLX101.
In one embodiment, the proliferative disorder is cancer, for example, a cancer described herein.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with one or more chemotherapeutic agents, for example, as described herein. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in a dose and / or dosage program described herein. In one embodiment, the subject is administered more than one dose of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, as described herein, and the agent that reduces or inhibits one or more symptoms of hypersensitivity is administered before each dose of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP.
In one embodiment, the method includes selecting a subject who has a proliferative disorder, for example, cancer, and who has experienced one or more symptoms of hypersensitivity, for example, has experienced one or more symptoms of hypersensitivity in a previous chemotherapeutic treatment, for the administration of an agent that reduces or inhibits one or more symptoms of hipersensibilid.ad and a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a conjugate, particle or camptothecin composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101. Symptoms of hypersensitivity include injection site reaction, dyspnea, hypotension, angioedema, urticaria, bronchospasm, and erythema.
In still another aspect, the description presents a method for treating a subject, for example, a human subject, with a proliferative disorder, for example, cancer, comprising: selecting a subject having a proliferative disorder, eg, cancer, which has increased the levels of KRAS and / or ST expression, for example, compared to a reference standard and / or a mutation in the KRAS gene and / or ST gene and administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a camptothecin conjugate, particle or composition of camptothecin attached to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP described herein, for example, CRLX101, to the subject in an amount effective to treat the cancer, to thereby treat the cancer.
In one embodiment, the conjugate includes an inhibitor of topoisomerase I and / or an inhibitor of topoisomerase II. In one embodiment, the conjugate includes a topoisomerase I inhibitor or combination of topoisomerase I inhibitors, for example, camptothecin, irinotecan, SN-38, topotecan, lamelarin D, and derivatives thereof. In one embodiment, the conjugate includes a topoisomerase II inhibitor or a combination of topoisomerase II inhibitors, e.g., eptoposide, tenoposide, doxorubicin, and derivatives thereof. In one embodiment, the conjugate includes a combination of one or more inhibitors of topoisomerase I and one or more inhibitors of topoisomerase II. In one embodiment, the conjugate of the topoisomerase inhibitor bound to the CDP is a camptothecin conjugate or camptothecin derivative linked to the CDP, for example, a camptothecin or camptothecin conjugate attached to the CDP described herein, for example, CRLX101.
In one embodiment, the subject has increased levels of KRAS and / or ST expression, for example, compared to a reference standard, and / or has a mutation in the KRAS and / or ST gene. In one embodiment, the subject has a mutation in one or more of: codon 12 of the KRAS gene (eg, a transversion G to T), codon 13 of the KRAS gene, codon 61 of the KRAS gene. In one embodiment, the subject has lung cancer (e.g., small cell lung cancer and / or non-small cell lung cancer), pancreatic cancer or colorectal cancer.
In one embodiment, cancer is a cancer described herein.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with one or more chemotherapeutic agents, for example, as described herein. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in a dose and / or dosage program described herein.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with one or more of the agents described herein. For example, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP can be administered in combination with an agent that reduces or inhibits one or more symptoms of hypersensitivity and / or an agent that increases urinary excretion and / or neutralizes one. or more urinary metabolites.
In another aspect, the disclosure features a unit dosage of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a camptothecin conjugate, particle or composition or camptothecin derivative linked to the CDP, eg, a conjugate. , particle or composition of camptothecin or camptothecin derivative linked to the CDP described herein, for example, CRLX101.
In one aspect, the disclosure features a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a conjugate, particle or composition derived from camptothecin bound to the CDP, for example, a conjugate, particle or camptothecin-derivative composition bound to the CDP described herein, and methods for making the conjugates, particles or compositions of the topoisomerase inhibitor bound to the CDP, eg, a conjugate, a particle or composition derived from camptothecin bound to the CDP, for example, a conjugate, particle or composition derived from camptothecin linked to the CDP described herein.
In one embodiment, the conjugate includes an inhibitor of topoisomerase I and / or an inhibitor of topoisomerase II. In one embodiment, the conjugate includes an inhibitor of topoisomerase I or combination of inhibitors of topoisomerase I, for example, irinotecan, SN-38, topotecan, lamelarin D and derivatives thereof. In one embodiment, the conjugate includes an inhibitor of topoisomerase II or a combination of inhibitors of topoisomerase II. for example, eptoposide, tenoposide, doxorubicin and derivatives thereof. In one embodiment, the conjugate includes a combination of one or more inhibitors of topoisomerase I and one or more inhibitors of topoisomerase II.
In one modality, CDP is not biodegradable.
In one modality, CDP is biocompatible.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, a conjugate, particle or composition derived from camptothecin, for example, a camptothecin derivative attached to the CDP described herein, includes a complex of inclusion between a topoisomerase inhibitor, for example, a camptothecin derivative, bound or conjugated to the CDP, for example, through a covalent bond, and another molecule in the CDP. In one embodiment, the conjugate of the topoisomerase inhibitor bound to the CDP forms a nanoparticle. In one embodiment, the conjugate of the topoisomerase inhibitor attached to the CDP that includes an inclusion complex forms a nanoparticle. The nanoparticle ranges in size from 10 to 300 nm in diameter, for example, 20 to 280, 30 to 250, 30 to 200, 20 to 150, 30 to 100, 20 to 80, 30 to 70, 30 to 60 or 30. at 50 nm in diameter. In one embodiment, the nanoparticle has a diameter of 30 to 60 nm. In one embodiment, the composition comprises a population or a plurality of nanoparticles with an average diameter of 10 to 300 nm, for example, 20 to 280, 30 to 250, 30 to 200, 20 to 150, 30 to 100, 20 to 80. , 30 to 70, 30 to 60 or 30 to 50 nm. In one embodiment, the average nanoparticle diameter is from 30 to 60 nm. In one embodiment, the surface charge of the molecule is neutral or slightly negative. In some embodiments, the zeta potential of the particle surface is about -80 mV to about 50 mV, about -20 mV to about 20 mV, about -20 mV to about -10 mV or about -10 mV to around 0.
In one embodiment, the topoisomerase inhibitor (e.g., a camptothecin derivative, e.g., a camptothecin derivative described herein), conjugated to CDP is more soluble when conjugated to CDP than when it is not conjugated. with the CDP.
In one embodiment, the composition comprises a population, mixture or plurality of conjugates of the topoisomerase inhibitor bound to the CDP. In one embodiment, the population, mixture or plurality of conjugates of the topoisomerase inhibitor bound to the CDP comprises a plurality of different topoisomerase inhibitors conjugated to a CDP (for example, two different topoisomerase inhibitors are in the composition so that two different topoisomerase inhibitors are bound to a single CDP, or a first topoisomerase inhibitor is attached to a first CDP and a second topoisomerase inhibitor is attached to a second CDP and both conjugates of the inhibitor bound to the CDP are present in the composition).
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and the drawings and the claims.
BRIEF DESCRIPTION OF THE DRAWINGS FIGs. 1A and 1B are CT images (computed tomography) of a patient with metastatic pancreatic cancer before treatment (FIG 1A) and after six months of treatment with CRLX101 (FIG 1B). The patient received 6 mg / m2 of CRLX101 according to the program la.
FIGs. 2A and 2B are graphs describing the pharmacokinetic and toxicokinetic analysis of CRLX101 administered by intravenous administration. FIG. 2A shows the plasma plasma concentration-time profile for the conjugated CPT (squares) and unconjugated (triangles) with the polymer for the 1b-1 cohort (12 mg / m2). FIG. 2B shows the average urinary excretion of the conjugated CPT (black bars) and unconjugated (white bars) with the polymer in the first 48 hours after administration of CRLX101. The plasma concentrations for the CPT conjugated and unconjugated with the polymer were below the limit of quantification at 336 hrs (before the second dose) and, therefore, are not plotted in FIG. 2A.
FIGs. 3A-3C describe the immunohistochemistry and topoisomerase I activity of ovarian cancer cells from a patient treated with CRLX101, which show reduction after treatment of the topoisomerase I protein. FIG. 3A is an immunohistochemical staining of ascites cells collected before CRLX101 was administered. FIG. 3B is an immunohistochemical staining of ascites cells collected 2 days after treatment with CRLX101. FIG. 3C is a gel that describes the results of the enzyme activity assay of topoisomerase I in whole cell lysates.
FIG. 4 describes the structure and description of an example of camptothecin conjugate attached to the CDP known as "CRLX101" throughout this application. CRLX101 is used so interchangeable with the term CRLX101 (for example, as in Example 1).
Detailed description of the invention The present invention relates to therapeutic cyclodextrin-containing polymer (CDP) compositions designed for administration of the drug of a topoisomerase inhibitor, such as camptothecin or a camptothecin derivative. In certain embodiments, these cyclodextrin-containing polymers improve the stability and / or solubility of the drug and / or reduce the toxicity and / or improve the efficacy of the topoisomerase inhibitor when used in vivo.
In addition, by selecting a variety of linker groups that bind or couple the CDP to a topoisomerase inhibitor such as camptothecin or a camptothecin derivative and / or targeting ligands, the rate of drug release from the polymers can be attenuated. for a controlled administration. The invention also relates to methods for treating subjects with compositions described herein. The invention also relates to methods for carrying out a pharmaceutical business comprising the manufacture, licensing or distribution of kits containing or referring to the conjugates, particles or compositions of the topoisomerase inhibitor bound to the CDP described in I presented.
More generally, the present invention provides conjugates of biocompatible and water soluble polymers that comprise a biocompatible, water-soluble polymer covalently linked to the topoisomerase inhibitor through linkages that are cleaved under biological conditions to release the topoisomerase inhibitor.
The polymer conjugates presented in the methods described herein may be useful for improving the solubility and / or stability of a bioactive / therapeutic agent, such as camptothecin, reducing drug-drug interactions., reduce interactions with blood elements including plasma proteins, reduce or eliminate immunogenicity, protect the agent from metabolism, modulate the kinetics of drug release, improve circulation time, improve the half-life of the drug (for example, in serum or in selected tissues, such as tumors), attenuate toxicity, improve efficacy, normalize drug metabolism in subjects of different species, ethnicities and / or races, and / or provide targeted administration to specific cells or tissues.
In preferred embodiments, the topoisomerase inhibitor in the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP is camptothecin or a camptothecin derivative. As used herein, the term "camptothecin derivative" includes camptothecin analogs and camptothecin metabolites. For example, the camptothecin derivatives can have the following structure: Where R1 is H, OH, optionally substituted alkyl (e.g., optionally substituted with NRa2 or ORa, or SiRa3), or SiRa3; or R1 and R2 can be taken together to form an optionally substituted 5 to 8 membered ring (eg, optionally substituted with NRa2 or ORa); R2 is H, OH, NH2, halo, nitro, optionally substituted alkyl (eg, optionally substituted with NRa2 or ORa, NRa2, OC (= 0) NRa2, or OC (= 0) ORa); R3 is H, OH, NH2, halo, nitro, NRa2, OC (= 0) NRa2 or OC (= 0) ORa; R4 is H, OH, NH2, halo, CN or NRa2; or R3 and R4 taken together with the atoms to which they are attached form a ring of 5 or 6 members (for example forming a ring including -OCH20- or -OCH2CH20-); each Ra is independently H or alkyl; or two Ra, taken together with the atom to which they are attached form a ring of 4 to 8 members (for example, optionally containing an O or NRb); R is H or optionally substituted alkyl (e.g., optionally substituted with ORc or NRC2); Rc is H or alkyl; or, two Rc, taken together with the atom to which they are attached form a ring of 4 to 8 members and n = 0 or 1 In some embodiments, the camptothecin or camptothecin derivative is the compound as provided below.
In one embodiment, R1, R2, R3 and R4 of the camptothecin derivative are each H and n is 0.
In one embodiment, R1, R2, R3 and R4 of the camptothecin derivative are each H and n is 1.
In one embodiment, R1 of the camptothecin derivative is H, R2 is -CH2N (CH3) 2, R3 is -OH, R4 is H, and n is 0.
In one embodiment, R1 of the camptothecin derivative is - CH2CH3, R2 is H, R3 is: R4 is H and n is 0.
In one embodiment, R1 of the camptothecin derivative is -CH2CH3, R2 is H, R3 is -OH, R4 is H, and n is 0.
In one embodiment, R of the camptothecin derivative is tert-butyldimethylsilyl, R 2 is H, R 3 is -OH and R 4 is H and n is 0.
In one embodiment, R of the camptothecin derivative is tert-butyldimethylsilyl, R 2 is hydrogen, R 3 is -OH and R 4 is hydrogen and n is 1.
In one embodiment, R1 of the camptothecin derivative is tert-butyldimethylsilyl, R2, R3 and R4 are each H and n is 0.
In one embodiment, R1 of the camptothecin derivative is tert-butyldimethylsilyl, R2, R3 and R4 are each H and n is 1.
In one embodiment, R1 of the camptothecin derivative is -CH2CH2Si (CH3) 3 and R2, R3 and R4 are each H.
In one embodiment, R1 and R2 of the camptothecin derivative are taken together with the carbons to which they are attached to form an optionally substituted ring. In one embodiment, R and R2 of the camptothecin derivative are taken together with the carbons to which they are attached to form a 6-membered substituted ring. In one embodiment, the camptothecin derivative has the following formula: . In one embodiment, R3 is methyl and R4 is fluoro.
In one embodiment, R3 and R4 are taken together with the carbons to which they are attached to form an optionally substituted ring.
In one embodiment, R3 and R4 are taken together with the carbons to which they are attached to form a 6-membered heterocyclic ring. In one embodiment, the camptothecin derivative has the following formula: . In one embodiment, R1 is: do not.
In one embodiment, the camptothecin derivative has the following formula: In one embodiment, R1 is: do not.
In one modality, R is: is H, R3 is methyl, R4 is chloro; and n is 1 In one embodiment, R1 is -CH = NOC (CH3) 3, R2, R3 and R4 are each H and n is 0.
In one embodiment, R1 is -CH2CH2NHCH (CH3) 2, R2, R3 and R4 are each H and n is 0.
In one embodiment, R and R2 are H, R3 and R4 are fluoro and n is 1.
In one embodiment, each of R1, R3 and R4 are H, R2 is; NH2 and n is 0.
In one embodiment, each of R, R3 and R4 is H, R2 is N02 and n is 0.
An "effective amount" or "effective amount" refers to an amount of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP that is effective, at the time of single or multiple dosing administrations to a subject, to treat a cell or cure, mitigate, alleviate or improve a symptom of a disorder. An effective amount of the conjugate, particle or composition may vary according to factors such as the disease state, age, sex and weight of the individual and the ability of the compound to elicit a desired response in the individual. An "effective amount" is also an amount where any toxic or detrimental effect of the conjugate, particle or composition is overcome by the therapeutically beneficial effects.
As used herein, the term "subject" is intended to include both human and non-human animals. Examples of human subjects include a human patient having a disorder, for example, a disorder described herein, or a normal subject. The term "non-human animals" includes all vertebrates, e.g., non-mammals (such as chickens, amphibians and reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals, e.g., sheep, dog , cat, cow, pig, etc.
As used herein, the term "treating" or "treating" a subject having a disorder refers to subjecting the subject to a regimen, for example, the administration of a conjugate, particle or composition of the inhibitor of the topoisomerase attached to the CDP, so as to cure, mitigate, alleviate, alter, remedy, alleviate or improve at least one symptom of the disorder. Treating includes the administration of an effective amount to mitigate, alleviate, alter, cure, alleviate, ameliorate or affect the disorder or symptoms of the disorder. The treatment can inhibit the deterioration or aggravation of a symptom of a disorder.
An amount of a conjugate, particle or composition of the topoisomerase inhibitor linked to the CDP effective to prevent a disorder, or a "prophylactically effective amount" of the conjugate, particle or composition as used in the context of the administration of an agent to a subject, refers to subjecting the subject to a regimen, for example, the administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP in order to delay the onset of at least one symptom of the disorder compared to what would be observed in the absence of the regimen.
Conjugates, Particles and Compositions of the Topoisomerase Inhibitor attached to the CDP Herein are described conjugates of the topoisomerase inhibitor bound to the cyclodextrin-containing polymer ("CDP"), wherein one or more topoisomerase inhibitors are covalently bound to the CDP (e.g., directly or through a linker) . Conjugates of the topoisomerase inhibitor bound to the CDP include linear or branched cyclodextrin-containing polymers and polymers grafted with cyclodextrin. Examples of cyclodextrin-containing polymers that can be modified as described herein are described in U.S. Patent Nos. 7,270,808, 6,509,323, 7,091,192, 6,884,789, U.S. Publication Nos. 20040087024, 20040109888 and 20070025952.
Accordingly, in one embodiment, the conjugate of the topoisomerase inhibitor bound to the CDP is represented by the Formula where P represents a linear or branched polymer chain; CD represents a cyclic part, such as a part of cyclodextrin; l_i, l_2 and L3, independently for each occurrence, may be absent or represent a linker group; D, independently for each occurrence, represents a topoisomerase inhibitor or a prodrug thereof (eg, a camptothecin or camptothecin derivative); T, independently for each occurrence, represents a targeting ligand or precursor thereof; a, m and v, independently for each occurrence, represent integers in the range of 1 to 10 (preferably 1 to 8, 1 to 5 or even 1 to 3); n and w, independently for each occurrence, represent an integer in the range of 0 to about 30,000 (preferably < 25,000, < 20,000, < 15,000, < 10,000, < 5,000, < 1,000, < 500, <100, < 50, < 25, < 10 or even < 5) & b represents an integer in the range of 1 to about 30,000 (preferably < 25,000, < 20,000, < 15,000, < 10,000, < 5,000, < 1,000, < 500, < 100, < 50 , < 25, < 10 or even < 5), wherein either P comprises parts of cyclodextrin or n is at least 1.
In some embodiments, one or more portions of the topoisomerase inhibitor in the conjugate of the topoisomerase inhibitor bound to the CDP can be replaced with another therapeutic agent, for example, another anti-cancer agent or anti-inflammatory agent. Examples of anticancer agents are described herein. Examples of anti-inflammatory agents include a steroid, for example, prednisone, and an NSAID.
In certain embodiments, P contains a plurality of cyclodextrin parts within the polymer chain as opposed to the cyclodextrin portions that are grafted to the pendant groups outside the polymer chain. Thus, in certain embodiments, the polymer chain of formula I further comprises n 'units of U, where n' represents an integer in the range of 1 to about 30,000, for example, of 4-100, 4. -50, 4-25, 4-15, 6-100, 6-50, 6-25 and 6-15 (preferably < 25,000, < 20,000, < 15,000, < 10,000, < 5,000, < 1,000, <500, < 100, < 50, < 25, < 20, < 15, < 10 or even < 5); and U is represented by one of the following formulas below: where CD represents a cyclic part, such as a part of cyclodextrin or derivative thereof; L-4, l_5, L6 and L7l independently for each occurrence, may be absent or represent a linker group; D and D ', independently for each occurrence, represent the same or different topoisomerase inhibitor or prodrug forms thereof (eg, a camptothecin or a derivative of camptothecin); T and T, independently for each occurrence, represent the same or different targeting ligand or precursor thereof; f e and, independently for each occurrence, represent an integer in the range of 1 and 10 and g and z, independently for each occurrence, represent an integer in the range of 0 and 10.
Preferably the polymer has a plurality of parts D or D '. In some embodiments, at least 50% of the U units have at least one D or D '. In some embodiments, one or more portions of the topoisomerase inhibitor in the topoisomeric conjugate bound to the CDP can be replaced with another therapeutic agent, eg, another anti-cancer agent or anti-inflammatory agent.
In preferred embodiments, L and L7 represent linker groups.
The CDP may include a polymer of polycation, polylanion or non-ionic. A polycationic or polyanionic polymer has at least one site carrying a positive or negative charge, respectively. In said certain modalities, at least one of the linking part and the cyclic part comprises said loaded site, so that each appearance of that part includes a loaded site. In some modalities, CDP is biocompatible.
In certain embodiments, the CDP may include polysaccharides, and other non-protein biocompatible polymers and combinations thereof, which contain at least one hydroxyl end group, such as polyvinylpyrrolidone, poly (oxyethylene) glycol (PEG), polysuccinic anhydride, polysebacic acid , PEG-phosphate, polyglutamate, polyethylene imine, divinyl ether maleic anhydride (DIVMA), cellulose, pullulans, inulin, polyvinyl alcohol (PVA), N- (2-hydroxypropyl) methacrylamide (HPMA), dextran and hydroxyethyl starch (HES), and have optional pending groups for grafting therapeutic agents, targeting ligands and / or parts of cyclodextrin. In certain embodiments, the polymer may be biodegradable, such as (acid) poly (lactic), (acid) poly (glycolic), poly (alkyi 2-cyanoacrylates), polyhydrated and polyorthoesters, or bioerodible, such as polylactide-glycolide copolymers and derivatives thereof, non-peptide polyamino acids, polyiminocarbonates, poly-alpha-amino acids, polyalkyl-cyano-acrylate, polyphosphazenes or acyloxymethyl polyaspartate and polyglutamate copolymers and mixtures thereof.
In another embodiment, the conjugate of the topoisomerase inhibitor attached to the CDP is represented by Formula II: ° di) where P represents a monomer unit of a polymer comprising parts of cyclodextrin; T, independently for each occurrence, represents a targeting ligand or a precursor thereof; L6, L7, Le, L9 and L-io, independently for each occurrence, may be absent or represent a linker group; CD, independently for each occurrence, represents a part of cyclodextrin or a derivative thereof; D, independently for each occurrence, represents a topoisomerase inhibitor or a prodrug form thereof (eg, a camptothecin or camptotheme derivative); m, independently for each occurrence, represents an integer in the range of 1 to 10 (preferably 1 to 8, 1 to 5 or even 1 to 3); or represents an integer in the range of 1 to about 30,000 (preferably < 25,000, < 20,000, < 15,000, < 1I0,000, < 5,000, < 1,000, < 500, < 100, < 50, < 25, < 10 or even < 5) and p, n and q, independently for each occurrence, represent an integer in the range of 0 to 10 (preferably 0 to 8, 0 to 5, 0 a 3 or even 0 to around 2), wherein each CD and D is preferably present at least 1 location (preferably at least 5, 10, 25 or even 50 or 100 locations) in the composite.
In some embodiments, one or more portions of the topoisomerase inhibitor in the conjugate of the topoisomerase inhibitor bound to the CDP can be replaced with another therapeutic agent, for example, another anti-cancer agent or anti-inflammatory agent. Examples of an anticancer agent are described herein. Examples of anti-inflammatory agents include a steroid, for example, prednisone, or an NSAID.
In another embodiment, the conjugate of the topoisomerase inhibitor bound to the CDP is represented by the formulas below: where CD represents a cyclic part, such as a part of cyclodextrin or derivative thereof; l_4, l_5, L6 and L7, independently for each occurrence, may be absent or represent a linker group; D and D ', independently for each occurrence, represent the same or different topoisomerase inhibitor or prodrug thereof (eg, a camptothecin or camptothecin derivative); T and? ', Independently for each occurrence, represent the same or different targeting ligand or precursor thereof; f e and, independently for each occurrence, represent an integer, in the range of 1 and 10 (preferably 1 to 8, 1 to 5 or even 1 to 3); g and z, independently for each occurrence, represent an integer in the range of 0 and 10 (preferably 0 to 8, 0 to 5, 0 to 3 or even 0 to about 2) and h represents an integer in the range of 1 and 30,000, for example, of 4-100, 4-50, 4-25, 4-15, 6-100, 6-50, 6-25 and 6-15 (preferably < 25,000, < 20,000, < 15,000, < 10,000, < 5,000, < 1,000, < 500, < 100, < 50, < 25, < 20, < 15, < 10 or even <5), wherein at least one occurrence (and preferably at least 5, 10 or even at least 20, 50 or 100 occurrences) of g represents an integer greater than 0.
Preferably the polymer has a plurality of parts of D or D '. In some embodiments, at least 50% of the repeating polymer units have at least one D or D '. In some embodiments, one or more portions of the topoisomerase inhibitor in the conjugate of the topoisomerase inhibitor bound to the CDP can be replaced with another therapeutic agent, for example, another anti-cancer agent or anti-inflammatory agent.
In preferred embodiments, L4 and L7 represent linker groups.
In said certain modalities, the CDP comprises cyclic parts that alternate with linking parts that connect the cyclic structures, for example, in linear or branched polymers, preferably linear polymers. The cyclic parts can be any suitable cyclic structure, such as cyclodextrins, crown ethers (eg, 18-crown-6, 15-crown-5, 12-crown-4, etc.), cyclic oligopeptides (eg, comprise from 5 to 10 amino acid residues), cryptands or cryptates (for example, crypting [2.2.2], crypting-2.1, 1 and complexes thereof), calixarenes or cavitands, or any combination thereof. Preferably, the cyclic structure is (or is modified to be) soluble in water. In certain embodiments, for example, for the preparation of a linear polymer, the cyclic structure is selected so that under polymerization conditions, exactly two parts of each cyclic structure are reactive with the linking portions, so that the resulting polymer comprises ( or consists essentially of) an alternative series of cyclic parts and linker parts, such as at least four of each type of part. Suitable dysfunctional cyclic parts include several that are commercially available and / or are amenable to preparation using published protocols. In certain embodiments, the conjugates are soluble in. water to a concentration of at least 0.1 g / mL, preferably at least 0.25 g / mL.
Thus, in certain embodiments, the invention relates to novel compositions of therapeutic cyclodextrin-containing polymeric compounds designed for the administration of drugs of a topoisomerase inhibitor. In certain embodiments, these CDPs improve the stability and / or solubility of the drug and / or reduce the toxicity and / or improve the efficacy of the topoisomerase inhibitor when used in vivo. Also, by selecting a variety of linking groups and / or targeting ligands, the rate of release of the topoisomerase inhibitor from the CDP can be attenuated for controlled administration.
In certain embodiments, the CDP comprises a linear cyclodextrin-containing polymer, for example, the polymer structure includes cyclodextrin portions. For example, the polymer can be a water-soluble linear cyclodextrin polymer produced by the ratio of at least one modified cyclodextrin derivative to carry a reactive site in each of exactly two positions, and reaction of the cyclodextrin derivative with a linker having exactly two reactive parts capable of forming a covalent bond with the reactive sites under polymerization conditions that promote the reaction of the reactive sites with the reactive parts to form covalent bonds between the linker and the cyclodextrin derivative, by which it occurs a linear polymer comprising alternative units of linkers and cyclodextrin derivatives. Alternatively, the polymer can be a water-soluble linear cyclodextrin polymer having a linear polymer structure, said polymer comprises a plurality of linker parts and substituted or unsubstituted cyclodextrin parts in the linear polymer structure, wherein each part of cyclodextrin, different from a part of cyclodextrin at the end of a polymer chain, is attached to two of said linker parts, each linker covalently linking two parts of cyclodextrin. In yet another embodiment, the polymer is a linear water-soluble cyclodextrin polymer comprising a plurality of cyclodextrin portions covalently linked by a plurality of linker portions, wherein each part of cyclodextrin, different from a part of cyclodextrin in the end of a polymer cell is joined to two linker parts to form a linear cyclodextrin polymer.
In some embodiments, the conjugate of the topoisomerase inhibitor bound to the CDP comprises a water soluble linear polymer conjugate comprising: parts of cyclodextrin; comonomers that do not contain cyclodextrin parts (comonomers) and a plurality of the topoisomerase inhibitor, wherein the conjugate of the topoisomerase inhibitor attached to the CDP comprises at least four, five, six, seven, eight, etc., parts of cyclodextrin and at least four, five, six, seven, eight, etc., comonomers. In some embodiments, the topoisomerase inhibitor is a topoisomerase inhibitor described in present, for example, the topoisomerase inhibitor is a camptothecin or camptothecin derivative described herein. The topoisomerase inhibitor can be linked to the CDP through a functional group such as a hydroxyl group or, where appropriate, an amino group.
In some embodiments, one or more portions of the topoisomerase inhibitor in the conjugate of the topoisomerase inhibitor bound to the CDP can be replaced with another therapeutic agent, for example, another anti-cancer agent or anti-inflammatory agent.
In some embodiments, said at least four parts of cyclodextrin and at least four comonomers are alternated in the conjugate of the topoisomerase inhibitor bound to the CDP. In some embodiments, the topoisomerase inhibitors are cleaved from said topoisomerase inhibitor conjugate bound to the CDP under biological conditions to release the topoisomerase inhibitor. In some embodiments, the cyclodextrin moieties comprise linkers to which the topoisomerase inhibitors bind. In some embodiments, topoisomerase inhibitors are linked through linkers.
In some embodiments, the comonomer comprises portions of at least two functional groups through which the reaction and binding of the cyclodextrin monomers was achieved. In some embodiments, the functional groups, which may be the same or different, terminal or internal, of each comonomer comprise an amino, acid, imidazole, hydroxyl, thio, acyl halide, -HC = CH-, group -C = C - or derived from them. In some embodiments, the two functional groups are the same and are located at the ends of the monomer precursor. In some embodiments, a comonomer contains one or more pending groups with at least one functional group through which the reaction was achieved and, thus, the binding of a topoisomerase inhibitor. In some embodiments, the functional groups, which may be the same or different, terminal or internal, of each pendant comonomer group comprise an amino, acid, imidazole, hydroxyl, thiol, acyl halide, ethylene, ethyne group or derivative thereof. same. In some embodiments, the pendant group is an aryl-substituted or unsubstituted branched, cyclic or straight C 1 -C 10 alkyl, optionally containing one or more heteroatoms within the chain or ring. In some embodiments, the cyclodextrin part comprises a part of alpha, beta or gamma cyclodextrin. In some embodiments, the topoisomerase inhibitor is at least 5%, 10%, 15%, 20%, 25%, 30% or 35% by weight of the conjugate of the topoisomerase inhibitor bound to the CDP.
In some embodiments, the comonomer comprises polyethylene glycol of 3,400 Da of molecular weight, the cyclodextrin part comprises beta-cyclodextrin, the theoretical maximum loading of the topoisomerase inhibitor in the conjugate of the topoisomerase inhibitor bound to the CDP is 13% by weight , and the topoisomerase inhibitor is 6-10% by weight of the conjugate of the topoisomerase inhibitor bound to the CDP. In some embodiments, the topoisomerase inhibitor is poorly soluble in water. In some embodiments, the solubility of the topoisomerase inhibitor is < 5 mg / ml at physiological pH. In some embodiments, the topoisomerase inhibitor is a hydrophobic compound with a logarithm P > 0.4, > 0.6, > 0.8, > 1, > 2, > 3, > 4 or > 5.
In some embodiments, the topoisomerase inhibitor is linked to the CDP through a second compound.
In some embodiments, administration of the conjugate of the topoisomerase inhibitor bound to the CDP to a subject causes the release of the topoisomerase inhibitor for a period of at least 6 hours. In some embodiments, administration of the conjugate of the topoisomerase inhibitor bound to the CDP to a subject causes the release of the topoisomerase inhibitor for a period of 2 hours, 3 hours, 5 hours, 6 hours, 8 hours, 10 hours, hours, 20 hours, 1 day, 2 days, 3 days, 4 days, 7 days, 10 days, 14 days, 17 days, 20 days, 24 days, 27 days up to a month. In some embodiments, upon administration of the conjugate of the topoisomerase inhibitor bound to the CDP to a subject, the rate of release of the topoisomerase inhibitor depends primarily on the rate of hydrolysis as opposed to the enzymatic cleavage.
In some embodiments, the conjugate of the topoisomerase inhibitor attached to the CDP has a molecular weight of 10,000-500,000. In some embodiments, the cyclodextrin parts make up at least about 2%, 5%, 10%, 20%, 30%, 50% u 80% of the conjugate of the topoisomerase inhibitor bound to CDP by weight.
In some embodiments, the conjugate of the topoisomerase inhibitor bound to the CDP is made by a method that provides precursors of modified cyclodextrin parts to carry a reactive site in each of exactly two positions, and the reaction of the cyclodextrin precursor parts with comonomer precursors having exactly two reactive parts capable of forming a covalent bond with the reactive sites under polymerization conditions that promote the reaction of the reactive sites with the reactive parts to form covalent bonds between the comonomers and parts of cyclodextrin, whereby a CDP is produced which comprises alternative units of a part of cyclodextrin and a comonomer. In some embodiments, the cyclodextrin part precursors are in a composition, said composition being substantially free of cyclodextrin portions having more than two positions modified to carry a reactive site (eg, parts of cyclodextrin having 1.3, 4, 5, 6 or 7 positions modified to carry a reactive site).
In some embodiments, a comonomer of the topoisomerase inhibitor conjugate bound to the CDP comprises a portion that is selected from the group consisting of: an alkylene chain, polysuccinic anhydride, poly-L-glutamic acid, poly (ethylene imine), an oligosaccharide and a chain of amino acids. In some embodiments, a comonomer of the conjugate of the topoisomerase inhibitor bound to the CDP comprises a polyethylene glycol chain. In some embodiments, a comonomer comprises a part that is selected from: polyglycolic acid chain and polylactic acid. In some embodiments, a comonomer comprises a hydrocarbylene group in which one or more methylene groups are optionally replaced by a group Y (provided that the Y groups are not linked together), wherein each Y, independently for each occurrence, is selected from aryl, heteroaryl, cycloalkyl, substituted or unsubstituted heterocycloalkyl u -O-, C (= X) (where X is NRi, O or S), -OC (O) -, -C (= 0) 0, -NR- , -NRÍCO-, -0 (0) 1 ^ -, -S (0) "- (where n is 0, 1 or 2), -OC (0) -NR. ,, - R CÍO ^ Rr, -NR , 1 -C (NR-i) -NRi- and -B (OR1) -; and R, independently for each occurrence, represents H or a lower alkyl.
In some embodiments, the conjugate of the topoisomerase inhibitor bound to the CDP is a polymer having attached thereto a plurality of parts of D of the following formula: where each L is independently a linker, and each D is independently an inhibitor of the topoisomerase, a prodrug derivative thereof, eg, a camptothecin or camptothecin derivative, or is absent; and each comonomer is independently a comonomer described in the presenté, and n is at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, provided that the polymer comprises at least one topoisomerase inhibitor and, in some embodiments, at least two parts of the topoisomerase inhibitor. In some embodiments, the molecular weight of the comonomer is from about 2000 to about 5000 Da (eg, from about 3000 to about 4000 Da (eg, about 3400 Da).
In some embodiments, the topoisomerase inhibitor is a topoisomerase inhibitor described herein, for example, the topoisomerase inhibitor is a camptothecin or camptothecin derivative described herein. The topoisomerase inhibitor can be linked to the CDP through a functional group such as a hydroxyl group or, where appropriate, an amino group. In some embodiments, one or more portions of the topoisomerase inhibitor in the conjugate of the topoisomerase inhibitor bound to the CDP can be replaced with another therapeutic agent, for example, another anti-cancer agent or anti-inflammatory agent.
In some embodiments, the conjugate of the topoisomerase inhibitor bound to the CDP is a polymer having attached thereto a plurality of parts of D of the following formula: wherein each L is independently a linker, and each D is independently a topoisomerase, a derivative of prodrug thereof, for example, a camptothecin or camptothecin derivative, or is absent, provided that the polymer comprises at least one topoisomerase inhibitor and, in some embodiments, at least two parts of the topoisomerase inhibitor; and wherein the group has an Mw of 3.4 kDa or less and n is at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 .
In some embodiments, the topoisomerase inhibitor is a topoisomerase inhibitor described herein, for example, the topoisomerase inhibitor is a camptothecin or camptothecin derivative described herein. The topoisomerase inhibitor may be linked to the CDP through a functional group such as a hydroxyl group or, where appropriate, an amino group. In some embodiments, one or more portions of the topoisomerase inhibitor in the conjugate of the topoisomerase inhibitor bound to the CDP can be replaced with another therapeutic agent, for example, another anti-cancer agent or anti-inflammatory agent.
In some modalities, less than all the parts of L are attached to parts of D, which means that, in some modalities, at least one D is absent. In some embodiments, the loading of the D parts in the conjugate of the topoisomerase inhibitor attached to the CDP is from about 1 to about 50% (eg, from about 1 to about 25%, around 5 to around 20% or around 5 to around 15%). In some embodiments, each L independently comprises an amino acid or a derivative thereof. In some embodiments, each L independently comprises a plurality of amino acids or derivatives thereof. In some embodiments, each L is independently a dipeptide or derivative thereof. In one embodiment, L is one or more of: alanine, arginine, histidine, Usin, aspartic acid, glutamic acid, serine, treoriin, asparaganin, glutamine, cysteine, glycine, proline, isoleucine, leucine, methionine, phenylalanine, tryptophan , tyrosine and valine.
In some embodiments, the conjugate of the inhibitor of the topoisomerase bound to the CDP is a polymer having attached thereto a plurality of L-D parts of the following formula: wherein each L is independently a linker or absent and each D is independently an inhibitor of the topoisomerase, a prodrug derivative thereof, eg, a camptothecin or camptothecin derivative, or is absent and where the group has an Mw of 3.4kDa or less and n is at least 4"5, 6, 7 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, as long as the polymer comprises at least one topoisomerase inhibitor and, in some embodiments, at least two parts of the topoisomerase inhibitor.
In some modalities, less than all the parts of C (= 0) are linked to parts of L-D, which means that, in some modalities, at least one L and / or D are absent. In some embodiments, the loading of the L, D and / or LD parts in the conjugate of the topoisomerase inhibitor bound to the CDP is from about 1 to about 50% (e.g., from about 1 to about 25). %, from around 5 to around 20% or from around 5 to around 15%). In some embodiments, each L independently comprises an amino acid or derivative thereof. In some embodiments, each L is glycine or a derivative thereof.
In some embodiments, one or more portions of the topoisomerase inhibitor in the conjugate of the topoisomerase inhibitor bound to the CDP can be replaced with another therapeutic agent, for example, another anti-cancer agent or anti-inflammatory agent.
In some embodiments, the conjugate of the topoisomerase inhibitor bound to the CDP is a polymer having the following formula: In some modalities, less than all the parts of C (= 0) they are attached to the parts which means that, in some embodiments, absent, provided that the polymer comprises at least one topoisomerase inhibitor and, in some embodiments, at least two parts of the topoisomerase inhibitor. In some modalities, the loading of the parts of conjugate of the topoisomerase inhibitor bound to the CDP is around 1 to about 50% (for example, about 1 to about 25%, about 5 to about 20% or about 5 to about 15%).
In some embodiments, one or more portions of the topoisomerase inhibitor in the conjugate of the topoisomerase inhibitor bound to the CDP can be replaced with another therapeutic agent, for example, another anti-cancer agent or anti-inflammatory agent.
In some embodiments, the conjugate of the topoisomerase inhibitor bound to the CDP will contain a topoisomerase inhibitor and at least one additional therapeutic agent. For example, a topoisomerase inhibitor and one or more other anti-cancer drugs, an immunosuppressant, an antibiotic or an anti-inflammatory agent can be grafted to the polymer through optional linkers. By selecting different linkers for different drugs, the release of said drug can be attenuated to achieve maximum dosage and efficacy.
C iclodextri ñas In certain embodiments, the cyclodextrin parts make up at least about 2%, 5% or 10% by weight, up to 20%, 30%, 50% or even 80% of the CDP by weight. In certain embodiments, the topoisomerase inhibitors or targeting ligands make up at least about 1%, 5%, 10% or 15%, 20%, 25%, 30% or even 35% of the CDP by weight. The amount of the average molecular weight (Mn) can also vary widely, but in general ranges from about 1,000 to about 500,000 daltons, preferably from about 5,000 to about 200,000 daltons and, even more preferably, around from 10,000 to around 100,000. More preferably, Mn varies between about 12,000 and 65,000 daltons. In other determined modalities, Mn varies between around 3000 and 150,000 daltons. Within a given sample of a polymer in question, a wide range of molecular weights may be present. For example, the molecules within the sample may have molecular weights that differ by a factor of 2, 5, 10, 20, 50, 100 or more, or that differ from the average molecular weight by a factor of 2, 5, 10, 20 , 50, 100 or more. Examples of cyclodextrin moieties include cyclic structures consisting essentially of 7 to 9 parts of saccharides, such as cyclodextrin and oxidized cyclodextrin. A cyclodextrin part optionally comprises a linker part that forms a covalent bond between the cyclic structure and the polymer structure, preferably having 1 to 20 atoms in the chain, such as alkyl chains, including dicarboxylic acid derivatives (such as , glutaric acid derivatives, succinic acid derivatives and the like) and heteroalkyl chains, such as oligoethylene glycol chains.
Cyclodextrins are cyclic polysaccharides containing D - (+) glucopyranose units of natural origin in an α- (1,4) -linkage. The most common cyclodextrins are alpha ((a) -cyclodextrins, beta () -cyclodextrins and gamma (Y) -cyclodextrins containing, respectively, six, seven or eight glucopyranose units.) Structurally, the cyclic nature of a cyclodextrin molds a form of donut or bocel having a hydrophobic or apolar inner cavity, the secondary hydroxyl groups are located on one side of the cyclodextrin batch and the primary hydroxyl groups are located on the other.Thus, using (p) -cyclodextrin as an example, A cyclodextring is often represented as follows: The side on which the secondary hydroxyl groups are located has a diameter wider than the side on which the secondary hydroxyl groups are located. The present invention contemplates covalent linkages to parts of cyclodextrin in the primary and / or secondary hydroxyl groups. The hydrophobic nature of the inner cyclodextrin cavity allows host-guest inclusion complexes of a variety of compounds, for example, adamantane. (Comprehensive Supramolecular Chemistry, Volume 3, JL Atwood et al., Eds., Pergamon Press (1996), T. Cserhati, Analytical Biochemistry, 225: 328-332 (1995), Husain et al., Applied Spectroscopy, 46: 652 -658 (1992); FR 2 665 169). The Additional methods for modifying polymers are described in Suh, J. and Noh, Y., Bioorg. Med. Chem. Lett. 1998, 8, 1327-1330.
In certain embodiments, the compounds comprise portions of cyclodextrin and wherein at least one or a plurality of the cyclodextrin portions of the topoisomerase inhibitor is oxidized. In certain embodiments, the cyclodextrin portions of P are alternated with linker parts in the polymer chain.
Comonomers In addition to a portion of cyclodextrin, the CDP may also include a comonomer, for example, a comonomer described herein. In some embodiments, a comonomer of the topoisomerase inhibitor conjugate bound to the CDP comprises a portion that is selected from the group consisting of: an alkylene chain, polysuccinic anhydride, poly-L-glutamic acid, poly (ethyleneimine), an oligosaccharide and an amino acid chain. In some embodiments, a comonomer of the topoisomerase inhibitor conjugate attached to the CDP comprises a polyethylene glycol chain. In some embodiments, a comonomer comprises a part that is selected from: polyglycolic acid chain and polylactic acid. In some embodiments, a comonomer comprises a hydrocarbylene group where one or more methylene groups are optionally replaced by a group Y (provided that the Y groups are not linked together), wherein each Y, independently for each occurrence, is selected from aryl , heteroaryl, cycloalkyl, substituted or unsubstituted heterocycloalkyl or -O-, C (= X) (wherein X is N 1t O or S), -OC (O) -, -C (= 0) 0, -NR- , - RTCO-, -CÍOJNR, -, -S (0) "- (where n is 0, 1 or 2), -OCfOJ-NR ,, -N 1-C (0) -NR1-, -NRi 1 - C (NR-i) -NRi- and -B (ORi) -; and R1t independently for each occurrence, represents H or a lower alkyl.
In some embodiments, a comonomer may be and / or may comprise a linker such as a linker described herein.
Examples of Conjugates, Particles and Compositions of Topoisomerase Inhibitor attached to the CDP In one embodiment, the conjugate of the topoisomerase inhibitor attached to the CDP forms a particle, eg, a nanoparticle. The particle may comprise a conjugate of the topoisomerase inhibitor bound to the CDP, for example, a plurality of conjugates of the topoisomerase inhibitor bound to the CDP, for example, conjugates of the inhibitor of the topoisomerase bound to the CDP having the same inhibitor of topoisomerase or different topoisomerase inhibitors. The compositions described herein comprise a conjugate of the topoisomerase inhibitor bound to the CDP or a plurality of conjugates of the topoisomerase inhibitor bound to the CDP. The composition may also comprise a particle or a plurality of particles described herein.
In one embodiment, the conjugate of the topoisomerase inhibitor bound to the CDP containing the inclusion complex forms a particle, eg, a nanoparticle. The nanoparticle ranges in size from 10 to 300 nm in diameter, for example, 20 to 280, 30 to 250, 40 to 200, 20 to 150, 30 to 100, 20 to 80, 30 to 70, 40 to 60 or 40 to 50 nm in diameter. In one embodiment, the particle is 50 to 60 nm, 20 to 60 nm, 30 to 60 nm, 35 to 55 nm, 35 to 50 nm or 35 to 45 nm in diameter.
In one embodiment, the surface charge of the molecule is neutral or slightly negative. In some embodiments, the zeta potential of the particle surface is about -80 mV to about 50 mV, about -20 mV to about 20 mV, about -20 mV to about -10 mV or about -10 mV to around 0.
In some embodiments, the conjugate of the topoisomerase inhibitor bound to the CDP is a polymer having the following formula C: formula C wherein L and L ', independently for each occurrence, linker, a -OH bond and, D, independently for each occurrence, is a topoisomerase inhibitor such as camptothecin ("CPT"), a camptothecin derivative or is absent , Y where the group has an Mw of 3.4kDa or less and n is at least 4, provided that at least one D is CPT or a camptothecin derivative. In some embodiments, at least 2 parts of D are CPT and / or a camptothecin derivative.
In some modalities, each L ', for each occurrence, is a cysteine. In some embodiments, the cysteine is linked to the cyclodextrin through a sulfide bond. In some embodiments, the cysteine is linked to the PEG-containing portion of the polymer through an amide bond.
In some embodiments, L is a linker (e.g., an amino acid such as glycine). In some modalities, L is absent. In some modalities, D-L together form In some embodiments, a plurality of parts of D is absent and in the same position in the polymer, the corresponding L is -OH.
In some embodiments, less than all the parts of C (= 0) of the part of cysteine in the polymer structure are attached to parts of it means that, some, it is absent in one or more positions of the polymer structure, provided that the polymer understand at least one in In some modalities, the loading of the parts in the conjugate of the topoisomerase inhibitor bound to the CDP is from about 1 to about 50% (for example, from about 1 to about 25%, from about 5 to about 20% or from about 5 to around 15%, for example, from around 6 to around 10%). In some modalities, the The charge in the CDP is about 6% to about 10% by weight of the total polymer.
In some embodiments, the conjugate of the topoisomerase inhibitor bound to the CDP of formula C is a polymer having the following formula: wherein L, independently for each occurrence, is a linker, a -OH bond and, D, independently for each occurrence, is a camptothecin ("CPT"), a camptothecin derivative or is absent, and where the group has an Mw of 3.4'kDa or less and n is at least 4, provided that at least one D is CPT or a camptothecin derivative. In some embodiments, at least 2 parts of D are CPT and / or a camptothecin derivative.
In some embodiments, the camptothecin conjugate bound to the CDP of formula C is a polymer having the following formula: where m and n are as defined above, and where less than all C (= 0) sites of the cysteine of the polymer structure are occupied as indicated above with the CPT-Gly, but instead are free acids , which means that the theoretical loading of the polymer is less than 100%.
In some embodiments, the camptothecin conjugate attached to the CDP is as provided in FIG. 4, and is shown below, which is referred to herein as "CRLX101".
In the previous structure: n = about 77 or the molecular weight day part of PEG is from about 3060 to about 3740 (for example, about 3400) Da; m = is around 10 to about 18 (for example, about 14); the molecular weight of the polymer structure (i.e., the polymer minus the CPT-gly, which causes parts of cysteine having a free -C (O) 0H) is from about 48 to about 85 kDa; the polydispersity of the polymer structure is less than about 2.2 and the load of the CPT in the polymer structure is around 6 to about 13% by weight, where 13% is the theoretical maximum, meaning that, in some cases, one or more of the cysteine parts have a -C (0) free OH (ie lacking CPT-gly).
In some embodiments, the polydispersity of the PEG in the previous structure is less than around 1.1.
In some embodiments, a camptothecin conjugate attached to the CDP described herein has an amine at the terminus and / or a carboxylic acid at the terminus.
In laza do res / Conecto res The CDPs described herein may include one or more linkers. In some embodiments, a linker can bind a topoisomerase inhibitor to a CDP. In some embodiments, a linker may link a camptothecin or a derivative of camptothecin to a CDP. In some embodiments, for example, when referring to a linker that binds a topoisomerase inhibitor to CDP, the linker can be referred to as a linker.
In certain embodiments, a plurality of the linker portions is linked to a topoisomerase inhibitor or prodrug thereof and cleaved under biological conditions.
Disclosed herein are conjugates of the CDP-bound topoisomerase inhibitor comprising a CDP covalently linked to a topoisomerase inhibitor through linkages that are cleaved under biological conditions to release the topoisomerase inhibitor. In certain modalities, a The conjugate of the topoisomerase inhibitor bound to the CDP comprises a topoisomerase inhibitor covalently bound to a polymer, preferably a biocompatible polymer, through a linker, for example, a linker, wherein the linker comprises a part that determines the selectivity and a self-cyclisation component that are covalently bound together in the connector, for example, between the polymer and the topoisomerase inhibitor.
In some embodiments, said topoisomerase inhibitors are covalently bound to the CDPs through functional groups comprising one or more heteroatoms, for example, hydroxy, thio I, carboxy, amino and amide groups. Such groups can be covalently bound to the subject polymers via linker groups as described herein, for example, biospendable linker groups, and / or via linkers, such as a linker comprising a part that determines the selectivity and a part of self-clustering that are covalently bound together.
In certain embodiments, the conjugate of the topoisomerase inhibitor bound to the CDP comprises a topoisomerase inhibitor covalently linked to the CDP through a linker, wherein the linker comprises a selfcyclization part. In some embodiments, the connector further comprises a part that determines the selectivity. Thus, one aspect of the invention relates to a polymer conjugate comprising a topoisomerase inhibitor covalently linked to a polymer, preferably a biocompatible polymer, through a linker, wherein the linker comprises a part that determines the selectivity and a part of autocyclization that are covalently linked together.
In some modalities, the part that determines the selectivity can be linked to the autocyclization part between the autocyclization part and the CDP.
In certain modalities, the part that determines the selectivity is a part that promotes the selectivity in the cleavage of the link between the part that determines the selectivity and the autocyclization part. Said part can, for example, promote enzymatic cleavage between the part that determines the selectivity and the autocyclization part. Alternatively, said part may promote cleavage between the part that determines the selectivity and the autocyclization part under acidic conditions or basic conditions.
In certain embodiments, the invention contemplates any combination of the foregoing. Those skilled in the art will recognize that, for example, any topoisomerase inhibitor of the invention in combination with any linker (eg, autocyclization part, any part that determines selectivity and / or any topoisomerase inhibitor) is found within of the scope of the invention.
In certain embodiments, the part that determines the selectivity is selected so that the bond is cleaved under acidic conditions.
In certain embodiments, where the part determining selectivity is selected such that the bond is cleaved under basic conditions, the part that determines the selectivity is a part of aminoalkylcarbonyloxyalkyl. In certain modalities, the part that determines the selectivity has a structure In certain embodiments, where the part determining the selectivity is selected such that the linkage is enzymatically cleaved, it can be selected such that a particular enzyme or class of enzymes cleaves the linkage. In said preferred embodiments, the part that determines the selectivity can be selected so that the bond is cleaved by a cathepsin, preferably cathepsin B.
In certain embodiments, the part that determines the selectivity comprises a peptide, preferably a dipeptide, tripeptide or tetrapeptide. In said certain embodiments, the peptide is a dipeptide which is selected from KF and FK. In certain embodiments, the peptide is a tripeptide selected from GFA, GLA, AVA, GVA, GIA, GVL, GVF and AVF. In certain modalities, the peptide is a tetrapeptide which is selected from GFYA and GFLG, preferably GFLG.
In said certain embodiments, a peptide, such as GFLG, is selected such that the bond between the part determining the selectivity and the autocyclization part is cleaved by a cathepsin, preferably cathepsin B.
In certain modalities, the part that determines the selectivity is represented by Formula A: I- S- J- Q- ¾ (A), Where S is a sulfur atom that is part of a disulfide bond; J is optionally substituted hydrocarbyl; Y Q is O or NR 3, wherein R 13 is hydrogen or alkyl.
In certain embodiments, J may be polyethylene I, polyethylene, polyester, alkenyl or alkyl. In certain embodiments, J may represent a hydrocarbyl group comprising one or more methylene groups, wherein one or more; Methylenes groups are optionally replaced by a Y group (provided that the Y groups are not linked together), where each Y, independently for each occurrence, is selected from aryl, heteroaryl, cycloalkyl, substituted or unsubstituted heterocycloalkyl or O, C ( = X) (where X is NR30, O or S), OC (O), -C (= 0) 0. NR30, R ^ O, C (0) NR30, S (0) n (where n is 0, 1 or 2), 0C (O) NR30, NR30C (O) NR30, NR301C (NR30) NR30- and B ( OR30); and R30, independently for each occurrence, it represents H or a lower alkyl. In certain embodiments, J can be substituted or unsubstituted lower alkylene, such as ethylene. For example, the part that determines the selectivity can be.
In certain modalities, the part that determines selectivity is represented by Formula B: where W is a direct bond or is selected from lower alkyl, NR14, S, O; S is sulfur; J, independently and for each occurrence, is hydrocarbyl or polyethylene glycol; Q is O or NR13, wherein R 3 is hydrogen or alkyl and R14 is selected from hydrogen and alkyl.
In certain embodiments, J may be substituted or unsubstituted lower alkyl, such as methylene. In said certain modalities, J can be an aryl ring. In certain embodiments, the aryl ring is a benzo ring. In certain modalities, W and S are in a ratio 1,2 in the ring & rile. In certain embodiments, the aryl ring may optionally be substituted with alkyl, alkenyl, alkoxy, aralkyl, aryl, heteroaryl, halogen, -CN, azido, -NRXRX, -C02ORx, -C (0) -NRxRx, -C (0) -Rx, -NRx-C (0) -R, -NRxS02Rx, -SRX, -S (0) Rx, -S02Rx, -S02NRxRx, - (C (Rx) 2) n-OR \ - (C (Rx) 2) n-NRxRx and - (C (Rx) 2) n-S02Rx; where R x is, independently for each occurrence, H or lower alkyl; and n is, independently for each occurrence, an integer from 0 to 2.
In certain embodiments, the aryl ring is optionally substituted with alkyl, alkenyl, alkoxy, aralkyl, aryl, heteroaryl, halogen, -CN, azido, -NRXRX, -C02OR, -C (O) -NR RX, -C (0) -Rx, -NRx-C (0) -Rx, -NRxS02Rx, -SRX, -S (0) Rx, -S02Rx, -S02NRxRx, - (C (Rx) 2) r-ORx, - (C (Rx) 2) nN RXRX and - (C (Rx) 2) n-S02Rx; where R x is, independently for each occurrence, H or lower alkyl; and n is, independently for each occurrence, an integer from 0 to 2.
In certain embodiments, J, independently and for each occurrence, is polyethylene glycol, polyethylene, polyester, alkenyl or alkyl.
In certain embodiments, independently and for each occurrence, the linker comprises a hydrocarbylene group comprising one or more methylene groups, wherein one or more methylene groups are optionally replaced by a group Y (provided that the Y groups are not linked together) , wherein each Y, independently for each occurrence, is selected from aryl, heteroaryl, cycloalkyl, substituted or unsubstituted heterocycloalkyl or O, C (= X) (where X is NR30, O or S), OC (O), - C (= 0) 0, NR30, NR, eO, C (0) NR30, S (0) n (where n is 0, 1 or 2), OC (0) NR30, NR30C (O) NR30, NR301C (NR30) NR30- and B (OR30); and R30, independently for each occurrence, represents H or a lower alkyl.
In certain embodiments, J, independently and for each occurrence, is substituted or unsubstituted lower alkylene. In certain embodiments, J, independently and for each occurrence, is substituted or unsubstituted lower ethylene.
In certain modalities, the part that determines the Selectivity is selected from and The part that determines the selectivity may include groups with bonds that are cleavable under certain conditions, such as disulfide groups. In certain embodiments, the part determining the selectivity comprises a disulfide-containing part, for example, comprising aryl group and / or alkyl attached to a disulfide group. In certain modalities, the part that determines the selectivity has a structure where Ar is a substituted or unsubstituted benzo ring; J is optionally substituted hydrocarbyl and is O ú NR13, wherein R13 is hydrogen or alkyl.
In certain modalities, Ar is not substituted. In certain embodiments, Ar is a 1,2-benzo ring. For example, suitable parts within Formula B include: In certain embodiments, the autocyclization part is selected so that after the split of the link between the part that determines the selectivity and the autocyclization part, cyclization occurs thus releasing the therapeutic agent. Said cleavage-cyclization-release cascade may occur sequentially in separate steps or substantially simultaneously. Thus, in certain modalities, there may be a temporal and / or spatial difference between the split and the autocyclization. The rate of the autocyclization cascade may depend on the pH, for example, a basic pH may increase the rate of autocyclization after cleavage. Autocyclization can have a half-life after in vivo introduction of 24 hours, 18 hours, 14 hours, 10 hours, 6 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 10 minutes, 5 minutes or 1 minute.
. In certain embodiments, the autocyclization part may be selected so that, after cyclization, a five or six member ring is formed, preferably a five member ring. In said certain embodiments, the five or six member ring comprises at least one heteroatom selected from oxygen, nitrogen or sulfur, preferably at least two, wherein the heteroatoms may be the same or different. In said certain embodiments, the heterocyclic ring contains at least one nitrogen, preferably two. In said certain embodiments, the autocyclization part is cyclized to form an imidazolidone.
In certain modalities, the autocyclization part has a structure where U is selected from NR and S; X is selected from O, NR5 and S, preferably O or S; V is selected from O, S and NR4, preferably O or NR4; R2 and R3 are independently selected from hydrogen, alkyl and alkoxy; or R2 and R3 together with the carbon atoms to which they are attached form a ring and R1, R4 and R5 are independently selected from hydrogen and alkyl.
In certain embodiments, U is NR1 and / or V is NR4, and R1 and R4 are independently selected from methyl, ethyl, propyl and isopropyl. In certain embodiments, both R and R4 are methyl. In certain embodiments, both R2 and R3 are hydrogen. In certain embodiments, R2 and R3 are independently alkyl, preferably lower alkyl. In certain embodiments, R2 and R3 together are - (CH2) n- where n is 3 or 4, thus forming a cyclopentyl or cyclohexyl ring. In certain modalities, the nature of R2 and R3 may affect the cyclization rate day part of autocyclization. In said certain embodiments, the cyclization rate would be expected to be greater when R2 and R3 together are the carbon atoms to which they are attached form a ring at the rate when R2 and R3 are independently selected from hydrogen, alkyl, and alkoxy. In certain modalities, U is linked to the autocyclization part.
In certain modalities, the autocyclization part is In certain embodiments, the part determining the selectivity can connect the autocyclization part through which the carbonyl heteroatom is attached, for example, amide, carbamate, carbonate, ester, thioester and urea linkages.
In certain embodiments, a topoisomerase inhibitor is covalently linked to a polymer via a linker, wherein the linker comprises a selectivity determining part and a selfcyclization part which are covalently linked together. In certain embodiments, the autocyclization part is selected so that after the cleavage of the link between the part determining the selectivity and the autocyclization part, the cyclization of the autocyclization part occurs, thus releasing the therapeutic agent. Illustratively, ABC can be a part that determines selectivity, and DEFGH can be a part of autocyclization, and ABC can be selected so that enzyme Y cleaves between C and D. Once the cleavage of the link between C and D progresses to a certain point, D cyclizes in H, thus releasing the topoisomerase X inhibitor or a prodrug thereof.
In certain embodiments, the topoisomerase X inhibitor may also comprise intervening components additional, including, but not limited to, another autocyclization portion or a leaving group linker, such as C02 or methoxymethyl, which spontaneously dissociates from the part of the molecule after the excision occurred.
In some embodiments, a linker can be and / or comprise an alkylene chain, a polyethylene glycol (PEG) chain, polysuccinic anhydride, poly-L-glutamic acid, poly (ethylene imine), an oligosaccharide, an amino acid (eg, glycine) or cysteine), a chain of amino acids or any other suitable linker. In certain modalities, the linker group itself may be stable under physiological conditions, such as an alkylene chain, or may be cleaved under physiological conditions, such as by an enzyme (eg, the linker contains a peptide sequence which is a substrate for a peptidase), or by hydrolysis (e.g., the linkage contains a hydrolysable group, such as an ester or thioester). The linker groups can be biologically inactive, such as a PEG, polygenic acid or polylactic acid chain, or they can be biologically active, such as an oligo or polypeptide which, when cleaved from the parts, binds to a receptor, deactivates an enzyme, etc. Several oligomeric linker groups are known in the art that are biologically compatible and / or bioerodible, and selection of the linkage can influence the final properties of the material, such as whether it is durable when implanted, whether it deforms or shrinks gradually after implantation. , or if it degrades gradually and is absorbed by the body. The linker group can be attached to the parts by any suitable bond or functional group, including carbon-carbon bonds, esters, ethers, amides, amines, carbonates, carbamates, sulfonamides, etc.
In certain embodiments, the linking group (s) of the present invention represents a hydrocarbylene group, where one or more methylene groups are optionally replaced by a group Y (provided that the groups Y are not linked together), where each Y, independently to each occurrence is selected from aryl, heteroaryl, cycloalkyl, substituted or unsubstituted heterocycloalkyl or O, C (= X) (wherein X is NR, O or S), OC (O), -C (= 0) , NR ,, NRTCO, C (0) NRI, S (0) n (where n is 0, 1 or 2), OC (0) NR ,, NRiC (0) NR- ,, NRi1C (NR-,) NRi- and BÍORT); and Rn, independently for each occurrence, represents H or a lower alkyl.
In certain embodiments, the linker group represents an amino acid derivative or non-derivative (eg, glycine or cysteine). In certain embodiments, linking groups with one or more carboxyl end groups can be conjugated with the polymer. In certain embodiments, one or more of these carboxyl end groups may be coated by covalent attachment to a therapeutic agent, a targeting portion or a cyclodextrin portion through a (thio) ester or amide linkage. In still other embodiments, linking groups with one or more hydroxyl, thiol or amino end groups may be incorporated into the polymer. In preferred embodiments, one or more of these end groups hydroxyl can be coated by covalent attachment to a therapeutic agent, a targeting part or a cyclodextrin part via a bond (thio) ester, amide, carbonate, carbamate, thiocarbonate or thiocarbamate. In certain embodiments, these (thio) ester, amide, (thio) carbonate or (thio) carbamate bonds can be biohydrolyzable, ie capable of being hydrolyzed under biological conditions.
In certain embodiments, a linker group represents a hydrocarbylene group in which one or more methylene groups are optionally replaced by a group Y (provided that the Y groups are not linked together), where each Y, independently for each occurrence, is selected from , aryl, heteroaryl, cycloalkyl, substituted or unsubstituted heterocycloalkyl or -O-, C (= X) (wherein X is NR, O or S), -OC (O) -, -C (= 0) 0, -NR-, -NRTCO-, -CÍÓJNRÍ-, -S (0) n- (where n is 0, 1 or 2), -OC (0) -NR ,, -NF ^ -CÍO'J-NR, - . - Ri-CÍ R ^ -NR! - and -B (ORi) -; and R-i, independently for each occurrence, represents H or a lower alkyl.
In certain embodiments, a linker group, for example, between a topoisomerase inhibitor and CDP, comprises a self-cyclization portion. In certain embodiments, a linker group, for example, between a topoisomerase inhibitor and CDP, comprises a part that determines the selectivity.
In certain embodiments as described herein, a linker group, for example, between a topoisomerase inhibitor and CDP, comprises a selfcyclization portion and a selectivity determining portion.
In certain embodiments as described herein, the topoisomerase inhibitor or targeting ligand is covalently linked to the linker group via a biohydrolyzable linkage (eg, an ester, amide, carbonate, cabamate or phosphate) .
In certain embodiments as described herein, the CDP comprises portions of cyclodextrin that alternate with linker portions in the polymer chain.
In certain embodiments, the linker moieties are linked to topoisomerase inhibitors or prodrugs thereof that are cleaved under biological conditions.
In certain embodiments, at least one linker that connects the topoisomerase inhibitor or prodrug thereof to the polymer comprises a group represented by the formula . where P is phosphorus; Or is oxygen; E represents oxygen or NR40; K represents hydrocarbyl; X is selected from OR42 or NR43R44 and R, R, R, R and R independently represent hydrogen or optionally substituted alkyl.
In certain modalities, E is N00 and R e is hydrogen.
In certain embodiments, K is lower alkylene (for example, ethylene).
In certain modalities, at least one linker comprises a group that is selected from and In certain modalities, X is OR.
In certain embodiments, the linker group comprises an amino acid or peptide or derivative thereof (eg, a glycine or cysteine).
In certain modalities ta! As described herein, the linker is connected to the topoisomerase inhibitor through a hydroxyl group. In certain embodiments as described herein, the linker is connected to the topoisomerase inhibitor through an ermine group.
In certain embodiments, the linker group that is connected to the topoisomerase inhibitor may comprise a self-cyclization part or a part that determines the selectivity, or both. In certain modalities, the part that determines the selectivity is a part that promotes the selectivity in the cleavage of the link between the part that determines the selectivity and the autocyclization part. Said part can, for example, promote enzymatic cleavage between the part that determines the selectivity and the autocyclization part. Alternatively, said part may promote cleavage between the part that determines the selectivity and the autocyclization part under acidic conditions or basic conditions.
In certain embodiments, any of the linker groups may comprise a self-cyclization part or a part that determines the selectivity, or both. In certain embodiments, the part that determines the selectivity can be linked to the autocyclization part between the autocyclization part and the polymer.
In certain embodiments, any of the linking groups may independently be an alkyl chain, a polyethylene glycol chain (PEG), polysuccinic anhydride, poly-L-glutamic acid, poly (ethylene imine), an oligosaccharide , a chain of amino acids or any other suitable linker. In certain embodiments, the linker group itself may be stable under physiological conditions, such as an alkyl chain, or may be cleaved under physiological conditions, such as by an enzyme (eg, the linker contains a peptide sequence that is a substrate for a peptidase), or by hydrolysis (for example, the linkage contains a hydrolysable group, such as an ester or thioester). Linker groups can be biologically inactive, such as a PEG, polyglycolic acid or polylactic acid chain, or they can be biologically active, such as an oligo or polypeptide which, when cleaved from the parts, binds to a receptor, deactivates a enzyme, etc. Several oligomeric linker groups are known in the art that are biologically compatible and / or bioerodible, and selection of the linkage can influence the final properties of the material, such as whether it is durable when implanted, whether it deforms or shrinks gradually after implantation. , or if it degrades gradually and is absorbed by the body. The linker group can be attached to the parts by any suitable bond or functional group, including carbon-carbon bonds, esters, ethers, amides, amines, carbonates, carbamates, sulfonamides, etc.
In certain embodiments, any of the linking groups can independently be an alkyl group wherein one or more methylene groups are optionally replaced by a group Y (provided that the Y groups are not linked together), where each Y independently for each occurrence , is selected from aryl, heteroaryl, carbocyclyl, heterocyclyl or O, C (= X) (wherein X is NR1, O or S), OC (O), -C (= 0) 0, NR1, NR1CO, C ( 0) NR1, S (0) "(where n is 0, 1 or 2), OC (0) NR1, NR1C (0) NR1, NR11 C (NR1) NR1- and B (OR1); and R1, independently for each occurrence, is H or lower alkyl.
In certain embodiments, the present invention contemplates a CDP, wherein a plurality of topoisomerase inhibitors are covalently bound to the polymer through linkages that are cleaved under biological conditions to release the therapeutic agents as described above, wherein the administration of the polymer to a subject causes the release of the therapeutic agent for a period of at least 2, 3, 5, 6, 8, 10, 15, 20, 24, 36, 48 or even 72 hours.
In some embodiments, conjugation of the topoisomerase inhibitor with CDP improves the aqueous solubility of the topoisomerase inhibitor and, therefore, bioavailability. Accordingly, in one embodiment of the invention, the topoisomerase inhibitor has a logarithm P > 0.4, > 0.6, > 0.8, > 1, > 2, > 3, > 4 or even > 5.
The conjugate of the topoisomerase inhibitor attached to the CDP of the present invention preferably has a molecular weight in the range of 10,000 to 500,000; 30,000 to 200,000; or even 70,000 to 150,000 amu.
In certain embodiments, the present invention contemplates reducing the release rate of the topoisomerase inhibitor by introducing various linkers and / or linking groups between the therapeutic agent and the polymer. Thus, in certain embodiments, the conjugates of the topoisomerase inhibitor bound to the CDP of the present invention are compositions for the controlled administration of the topoisomerase inhibitor.
Characteristics of the Conjugate of the Topoisomerase Inhibitor Linked to CDP In some embodiments, the CDP and / or the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP, as described herein, have polydispersities of less than about 3 or even less than about 2.
One embodiment of the present invention provides for an improved administration of a particular topoisomerase inhibitor by covalently linking one or more topoisomerase inhibitors to a CDP. Said conjugation can improve the aqueous solubility and, thus, the bioavailability of the topoisomerase inhibitor.
The conjugates, particles and compositions of the topoisomerase inhibitor attached to the CDP described herein preferably have molecular weights in the range of 10,000 to 500,000; 30,000 to 200,000; or even 70,000 to 150,000 amu. In certain embodiments, as described herein, the compound has an average molecular weight (Mn) amount between 1,000 to 500,000 amu, or between 5,000 to 200,000 amu, or between 10,000 to 100,000 amu. One method for determining molecular weight is by gel permeation chromatography ("GPC"), for example, mixed bed columns, CH2Cl2 solvent, light scattering and dn / dc offline. Other methods are known in the art.
In certain embodiments as described herein, the conjugate, particle or composition of the CDP topoisomerase inhibitor is biodegradable or bioerodible.
In certain embodiments as described herein, the topoisomerase inhibitor, camptothecin, camptothecin derivative or prodrug thereof composes at least 3% (e.g., at least about 5%) by weight of the polymer. In certain embodiments, the topoisomerase inhibitor, for example, camptothecin, camptothecin derivative or prodrug thereof composes at least 20% by weight of the compound. In certain embodiments, the topoisomerase inhibitor, for example, camptothecin, camptothecin derivative or prodrug thereof composes at least 5%, 10%, 15% or at least 20% by weight of the compound.
The conjugates, particles or compositions of the topoisomerase inhibitor bound to the CDP of the present invention may be useful for improving the solubility and / or stability of a topoisomerase inhibitor, reducing drug-drug interactions., reduce interactions with blood elements including plasma proteins, reduce or eliminate immunogenicity, protect the topoisomerase inhibitor from metabolism, modulate the kinetics of drug release, improve circulation time, improve the half-life of the inhibitor of the topoisomerase (eg, in serum or in selected tissues, such as tumors), attenuate toxicity, improve efficacy, normalize the metabolism of the topoisomerase inhibitor in subjects of different species, ethnicities and / or races, and / or provide an administration directed to specific cells or tissues.
In other embodiments, the conjugate, particle or composition of the CDP topoisomerase inhibitor can be a flexible or flowable material. When the CDP used is flowable in itself, the composition of the CDP of the invention, even though it is viscous, does not need to include a biocompatible solvent to be flowable, although there may still be trace or residual amounts of the biocompatible solvents.
While it is possible that the biodegradable polymer or the biologically active agent can be dissolved in a small amount of a solvent that is not toxic to more efficiently produce a monolithic and amorphous distribution or a fine dispersion of the biologically active agent in the flexible composition or flowable, it is an advantage of the invention that, in a preferred embodiment, no solvent is needed to form a flowable composition. Likewise, the use of solvents is preferably avoided since, once a solvent-containing polymer composition is completely or partially placed inside the body, the solvent is dissipated or diffused away from the polymer and must be processed and eliminated by the body, which creates an additional limit on the elimination capacity of the body at a time when the disease (and / or other treatments for the disease) may have already affected it in a harmful way.
However, when a solvent is used to facilitate mixing or to maintain the fluidity of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, it should be nontoxic, otherwise biocompatible, and should be used in relatively small amounts. . Solvents that are toxic should not be used in any material to be placed, even partially, within a living body. Said solvent should also not cause irritation or tissue necrosis at the administration site.
Examples of suitable biocompatible solvents, when used, include N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, caprolactam , oleic acid or 1 -dodecylazacylcoheptanone. Preferred solvents include N-methylpyrrolidone, 2-pyrrolidone, dimethyl sulfoxide and acetone given their solubility and biocompatibility.
In certain embodiments, the conjugates, particles and compositions of the topoisomerase inhibitor bound to the CDP are soluble in one or more common organic solvents for ease of manufacture and processing. Common organic solvents include such solvents as chloroform, dichloromethane, dichloroethane, 2-butanone, butyl acetate, ethyl butyrate, acetone, ethyl acetate, dimethylacetamide, N-methylpyrrolidone, dimethylformamide and dimethylsulfoxide.
In certain embodiments, the conjugates, particles and compositions of the topoisomerase inhibitor attached to the CDP described herein, upon contact with body fluids, undergo gradual degradation. The life of a biodegradable polymer depends, among other things, on its molecular weight, crystallinity, biostability and the degree of crosslinking. In general, the higher the molecular weight, the greater the degree of crystallinity and the greater the biostability, the slower the biodegradation.
If a composition in question is formulated with a topoisomerase inhibitor or other material, it generally results in the release of the topoisomerase inhibitor or other material for a sustained or extended period compared to the release of an isotonic saline solution. Said release profile may result in prolonged administration (for, say, 1 to about 2,000 hours or, alternatively, about 2 to about 800 hours) of effective amounts (eg, about 0.0001 mg / kg / hour). at about 10 mg / kg / hour, for example, 0.001 mg / kg / hour, 0.01 mg / kg / hour, 0.1 mg / kg / hour, 1.0 mg / kg / hour) of the topoisomerase inhibitor or any other material associated with the polymer.
A variety of factors can affect the desired rate of hydrolysis of conjugates, particles and compositions of the topoisomerase inhibitor bound to the CDP, the softness and flexibility of the resulting solid matrix, velocity and extent of release of the bioactive material. Some of said factors include the selection / identity of several subunits, the enantiomeric or diastereomeric purity of the monomeric subunits, the homogeneity of subunits found in the polymer and the length of the polymer. For example, the present invention contemplates heteropolymers with several linkages and / or the inclusion of other monomeric elements in the polymer, to control, for example, the rate of biodegradation of the matrix.
For a further illustration, a wide range of degradation rates can be obtained by adjusting the hydrophobicities of the structures or side chains of the polymers while still maintaining sufficient biodegradability for the intended use for any polymer. Said result can be achieved by varying various functional groups of the polymer. For example, the combination of a hydrophobic structure and a hydrophilic bond produces a heterogeneous degradation since the cleavage is promoted while the penetration of water is resisted.
A generally accepted protocol in the field can be used to determine the rate of release of a therapeutic agent such as a topoisomerase inhibitor or other material loaded into the conjugates, particles or compositions of the invention. topoisomerase inhibitor bound to CDP involves the degradation of any of said matrices in a 0.1 M PBS solution (pH 7.4) at 37 ° C, an assay known in the art. For purposes of the present invention, the term "PBS protocol" is used herein to refer to said protocol.
In such cases, the rates of release of various conjugates, particles or compositions of the topoisomerase inhibitor bound to the CDP of the present invention can be compared by subjecting them to said protocol. In certain cases, it may be necessary to process polymer systems in the same way to allow direct and relatively accurate comparisons of different systems to be performed. For example, the present invention teaches several different methods for formulating the conjugates, particles and compositions of the topoisomerase inhibitor bound to the CDP. Such comparisons may indicate that any conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP releases the incorporated material at a rate from about 2 or less to about 1000 or faster than another polymer system.
Alternatively, a comparison may reveal a difference in speeds of about 3, 5, 7, 10, 25, 50, 100, 250, 500 or 750 times. Still greater velocity differences are contemplated by the present invention and release rate protocols.
In certain embodiments, when formulated in a certain way, the release rate for the conjugates, particles and compositions of the topoisomerase inhibitor nested in the CDP of the present invention may be present as mono or biphasic.
The release of any material incorporated in the polymer matrix, which is often provided as a microsphere, can be characterized in certain cases by an increased initial release rate, which can be released from about 5 to about 50% or more of any incorporated material or, alternatively, about 10, 15, 20, 25, 30 or 40%, followed by a release rate of lesser magnitude.
The release rate of any incorporated material can also be characterized by the amount of said material released per day per mg of the polymer matrix. For example, in certain embodiments, the rate of release may vary from about 1 ng or less of any material incorporated per day per mg of the polymer system to about 500 or more ng / day / mg. Alternatively, the release rate can be around 0.05, 0.5, 5, 10, 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450 or 500 ng / day / mg . In still other modalities, the release rate of any incorporated material may be 10,000 ng / day / mg or even greater. In certain cases, the materials incorporated and characterized by said release rate protocols may include therapeutic agents, fillers and other substances.
In another aspect, the rate of release of any material from any conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP of the present invention can be presented as the half-life of said material in the matrix.
In addition to the modality involving protocols for the in vitro determination of release rates, in vivo protocols are also contemplated in the present invention, by which in certain cases the release rates for polymeric systems can be determined in vivo. Other assays useful for determining the release of any material from the polymers of the present systems are known in the art.
Physical Structures of the Conjugates, Particles or Compositions of the Topoisomerase Inhibitor attached to the CDP The conjugates, particles or compositions of the topoisomerase inhibitor bound to the CDP can have a variety of forms. For example, in certain embodiments, the conjugates of the topoisomerase inhibitor bound to the CDP may be presented in the form of microparticles or nanoparticles. The microspheres typically comprise a biodegradable polymer matrix incorporating a drug. The microspheres can be formed by a wide variety of techniques known to those skilled in the art. Examples of microsphere-forming techniques include, but are not limited to, (a) phase separation by emulsification and subsequent evaporation of the organic solder (including complex emulsion methods, such as oil-in-water emulsions, water-in-oil emulsions and water emulsions). -water-oil); (b) phase separation (coacervation); (c) molten dispersion; (d) interfacial deposition; (e) in situ polymerization; (f) spray drying and spray freezing; (g) suspension coating by air and (h) skillet coating and atomizer. These methods, as well as properties and characteristics of microspheres are described in, for example, U.S. Patent No. 4,438,253; U.S. Patent No. 4,652,441; U.S. Patent No. 5,100,669; U.S. Patent 5,330,768; U.S. Patent 4,526,938; U.S. Patent No. 5,889,110; U.S. Patent 6,034,175 and European Patent 0258780, the contents of which are incorporated herein by this reference in its entirety.
To prepare microspheres, various methods may be employed depending on the desired application of the delivery vehicles. Suitable methods include, but are not limited to, spray drying, freeze drying, air drying, vacuum drying, fluidized bed drying, grinding, coprecipitation, and critical fluid extraction. In the case of spray drying, air drying, vacuum drying, fluidized bed drying and extraction of critical fluids, the components (stabilizing polyol, bioactive material, buffers, etc.) are first dissolved or suspended in aqueous conditions. In the milling house, the components are mixed in the dry form and ground by any method known in the art. In the case of co-precipitation, the components are mixed under organic conditions and processed as described below. The spray drying can be used to charge the stabilizing polyol with the bioactive material. The components are mixed under aqueous conditions and dried using precision nozzles to produce extremely uniform droplets in a drying chamber. Suitable spray drying machines include, but are not limited to, Buchi, NIRO, APV and Lab plant spray dryers used in accordance with the manufacturer's instructions.
The shape of the microparticles and nanoparticles can be determined by scanning electron microscopy. Spherical-shaped nanoparticles are used in certain modalities for circulation through the bloodstream. If desired, the particles can be manufactured using techniques known in other forms that are more useful for a specific application.
In addition to the intracellular administration of a topoisomerase inhibitor, it is also possible that particles of the CDP topoisomerase inhibitor conjugates, such as microparticles or nanoparticles, may undergo endocytosis, thereby gaining access to the cell. The frequency of this endocytosis process will probably depend on the size of any particle.
In one embodiment, the surface charge of the molecule is neutral or slightly negative. In some embodiments, the zeta potential of the particle surface is around -80 mV to around 50 mV.
CDP, Methods for Performing the Same and Methods for Conjugating PDCs with Topoisomerase Inhibitors In general, the conjugates, particles and compositions of the topoisomerase inhibitor bound to the CDP described herein can be prepared in one of two ways: monomers carrying topoisomerase inhibitors, targeting ligands and / or cyclodextrin portions can be polymerized , or the structures of the polymers can be derivatized with topoisomerase inhibitors, targeting ligands and / or cyclodextrin portions. Examples of methods for performing the CDPs and conjugates, particles and compositions of the topoisomerase inhibitor bound to the CDP are described in, for example, US Pat. No. 7,270,808, the entire contents of which are incorporated herein by reference. .
The CDPs described herein can be made using a variety of methods including those described herein. In some embodiments, a CDP can be made by: proportion of precursors of cyclodextrin parts; proportion of comonomer precursors that do not contain parts of cyclodextrin (comonomer precursors) and copolymerization of said cyclodextrin precursor parts and comonomer precursors to thereby make a CDP where CDP comprises at least four parts of cyclodextrin and at least four comonomers.
In some embodiments, said at least four parts of cyclodextrin and at least four comonomers alternate in the linear water-soluble polymer. In some embodiments, the method includes the proportion of modified cyclodextrin precursor portions to carry a reactive site in each of exactly two positions, and the reaction of the cyclodextrin precursor parts with comonomer precursors having exactly two reactive parts capable of of forming a covalent bond with the reactive sites under polymerization conditions that promote the reaction of the reactive sites with the reactive parts to form covalent bonds between the comonomers and parts of cyclodextrin, whereby a CPP is produced which comprises alternative units of a part of cyclodextrin and a comonomer.
In some embodiments, the cyclodextrin monomers comprise linkers to which the inhibitor may additionally bind to the topoisomerase.
In some embodiments, the comonomer precursor is a compound that contains at least two functional groups through which the reaction was achieved and, thus, the binding of the cyclodextrin parts. In some embodiments, the functional groups, which may be the same or different, terminal or internal, of each comonomer precursor comprise its amino, acid, imidazole, hydroxyl, thio, acyl halide, -HC = CH-, group -C = Co derived from them. In some embodiments, the two functional groups are the same and are located at the ends of the monomer precursor. In some embodiments, a comonomer contains one or more pending groups with at least one functional group through which the reaction can be achieved and, thus, the binding of a therapeutic agent. In some embodiments, the functional groups, which may be the same or different, terminal or internal, of each comonomer-pending group comprise an amino, acid, imidazole, hydroxyl, thiol, acyl halide, ethylene, ethyne group or derivative thereof. same. In some embodiments, the pendant group is an aryl-substituted or unsubstituted branched, cyclic or straight C 1 -C 10 alkyl or aryl alkyl optionally containing one or more heteroatoms within the chain or ring.
In some embodiments, the cyclodextrin part comprises a part of alpha, beta or gamma cyclodextrin.
In some embodiments, the CDP is suitable for binding a sufficient topoisomerase inhibitor so that at least 3%, 5%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30% or even 35% by weight of the CDP, when conjugated, is inhibitor of topoisomerase.
In some embodiments, the CDP has a molecular weight of 10,000-500,000 amu. In some modalities, the parts of cyclodextrin make up at least about 2%, 5%, 10%, 20%, 30%, 50% or 80% of the CDP by weight.
In some modalities, a CDP of the following formula can be made using the scheme below: where R has the form: which comprises the steps of: reacting a compound of the formula below: with a compound of the formula below: where the group has an Mw of 3.4kDa or less and n has at least four, in the presence of a solvent non-nucleophilic organic base.
In some modalities, it is In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is DMSO.
In some embodiments, the method also includes dialysis and lyophilization steps.
In some modalities, a CDP provided below can be made using the scheme below: where R has the form: with a compound provided below: wherein the group m has a Mw of 3.4kDa in the presence of a non-nucleophilic organic base in DMSO and dialyzing and lyophilizing the following polymer The present invention further contemplates CDPs and conjugates bound to CDP synthesized using the bicysteine monomer attached to the CD and a di-NHS ester such as PEG-DiSPA or PEG-BTC, as shown in Scheme I.
Scheme I Scheme XIII, as provided above, includes embodiments where gly-CPT is absent in one or more positions as provided above. This can be achieved, for example, when less than 100% yield is achieved when the CPT is coupled to the polymer and / or when less than an equivalent amount of the CPT is used in the reaction. Accordingly, the loading of the topoisomerase inhibitor, such as camptothecin, by weight of the polymer, can vary. Therefore, while Scheme XIII describes CPT in each cysteine residue of each polymer subunit, the CDP-CPT conjugate may have less than 2 CPT molecules bound to any given polymer subunit of the CDP. For example, in one embodiment, the CDP-CTP conjugate includes several polymer subunits and each of the polymer subunits can independently include two, one or no CPT bound in each cysteine residue of the polymer subunit. In addition, the particles and compositions may include CDP-CPT conjugates having two, one or no CPT bound in each cysteine residue of each polymer subunit of the CDP-CTP conjugate and the conjugates include a mixture of CDP-CTP conjugates which may vary in relation to the amount of CPTs bound to the gly in each of the polymer subunits of the conjugates in the particle or composition.
In some embodiments, a conjugate of the topoisomerase inhibitor bound to the CDP can be made by providing a CDP comprising parts of cyclodextrin and comonomers that do not contain portions of cyclodextrin (comonomers), where the cyclodextrin portions and the comonomers are alternated in the CDP and wherein the CDP comprises at least four parts of cyclodextrin and at least four comonomers; and attaching a topoisomerase inhibitor to CDP.
In some embodiments, one or more portions of the topoisomerase inhibitor in the conjugate of the topoisomerase inhibitor bound to the CDP can be replaced with another therapeutic agent, for example, another anti-cancer agent or anti-inflammatory agent.
In some embodiments, the topoisomerase inhibitor is attached to the linear water-soluble polymer through a linker. In some embodiments, the topoisomerase inhibitor is attached to the linear water-soluble polymer through a linkage that is cleaved under biological conditions to release the topoisomerase inhibitor. In some embodiments, the topoisomerase inhibitor is attached to the linear water-soluble polymer in a cyclodextrin portion or a comonomer. In some embodiments, the topoisomerase inhibitor is attached to the linear water-soluble polymer through an optional linker to a portion of a cyclodextrin or a comonomer.
In some embodiments, the cyclodextrin moieties comprise linkers to which the therapeutic agents bind.
In some embodiments, the CDP is made by a process comprising: providing precursors of cyclodextrin parts, providing comonomer precursors and copolymerizing said precursors of cyclodextrin parts and comonomer precursors to thereby perform a CDP comprising portions of cyclodextrin and comonomers. In some modalities, the CDP is conjugated with an inhibitor of topoisomerase such as camptothecin, to provide a conjugate of the topoisomerase inhibitor bound to the CDP.
In some embodiments, the method includes the proportion of modified cyclodextrin precursor portions to carry a reactive site in each of exactly two positions, and the reaction of the cyclodextrin precursor portions with comonomer precursors having exactly two reactive parts capable of of forming a covalent bond with the reactive sites under polymerization conditions that promote the reaction of the reactive sites with the reactive parts to form covalent bonds between the comonomers and parts of cyclodextrin, whereby a CDP is produced which comprises alternative units of a part of cyclodextrin and a comonomer.
In some embodiments, the topoisomerase inhibitor is linked to the CDP through a linker. In some embodiments, the linker is cleaved under biological conditions.
In some embodiments, the topoisomerase inhibitor makes at least 5%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30% or even 35% by weight of the conjugate of the Topoisomerase inhibitor bound to CDP.
In some embodiments, the comonomer comprises polyethylene glycol of 3,400 Da of molecular weight, the cyclodextrin part comprises beta-cyclodextrin, the theoretical maximum charge of camptothecin in a camptothecin conjugate attached to the CDP is 13% and the camptothecin is 6-10% in Weight of the camptothecin conjugate bound to the CDP.
In some embodiments, the comonomer precursor is a compound that contains at least two functional groups through which the reaction was achieved and, thus, the binding of the cyclodextrin portions. In some embodiments, the functional groups, which may be the same or different, terminal or internal, of each comonomer precursor comprise its amino, acid, imidazole, hydroxyl, thio, acyl halide, -HC = CH-, group-, C = Co derived from them. In some embodiments, the two functional groups are the same and are located at the ends of the monomer precursor. In some embodiments, a comonomer contains one or more pending groups with at least one functional group through which the reaction is achieved and, thus, the binding of a therapeutic agent. In some embodiments, the functional groups, which may be the same or different, terminal or internal, of each comonomer-pending group comprise an amino, acid, imidazole, hydroxyl, thiol, acyl halide, ethylene, ethyne group or derivative thereof. same. In some embodiments, the pendant group is an aryl or substituted or unsubstituted branched, cyclic or straight C 1 -C 10 alkyl optionally containing one or more heteroatoms within the chain or ring.
In some embodiments, the cyclodextrin part comprises a part of alpha, beta or gamma cyclodextrin.
In some embodiments, the topoisomerase inhibitor is poorly soluble in water.
In some embodiments, administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP to a subject causes the release of the topoisomerase inhibitor for a period of at least 6 hours. In some embodiments, administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP to a subject causes the release of the topoisomerase inhibitor for a period of 6 hours to a month. In some embodiments, upon administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP to a subject, the rate of release of the topoisomerase inhibitor depends primarily on the rate of hydrolysis as opposed to the enzymatic cleavage.
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP has a molecular weight of 10,000-500,000 amu.
In some embodiments, the cyclodextrin parts make up at least about 2%, 5%, 10%, 20%, 30%, 50% or $ 0% of the polymer by weight.
In some embodiments, a conjugate of the polymer bound to the CDP can be made in the following manner: and coupling the polymer with a plurality of L-D parts, wherein L is a linker or absent and D is a topoisomerase inhibitor such as camptothecin or a camptothecin derivative, to provide: has at least 4, where in the final product, L can be a linker, a bond or OH, and D can be a topoisomerase inhibitor (e.g., camptothecin or a camptothecin derivative) or is absent.
In some embodiments, one or more portions of the topoisomerase inhibitor in the conjugate of the topoisomerase inhibitor bound to the CDP can be replaced with another therapeutic agent, for example, another anti-cancer agent or anti-inflammatory agent.
The reaction scheme, as provided above, includes embodiments where L-D is absent in one or more positions as provided above. This can be achieved, for example, when less than 100% yield is achieved when the linker of the topoisomerase inhibitor is coupled to the polymer and / or when less than an equivalent amount of the topoisomerase inhibitor linker is used in the reaction. . Accordingly, the charge of the topoisomerase inhibitor, by weight of the polymer, can vary, for example, the charge of the topoisomerase inhibitor can be at least about 3% by weight, for example, at least about 5%, at least about 8%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15% or at least less around 20%.
In some embodiments, at least a portion of the L parts of L-D is absent. In some embodiments, each L is independently an amino acid or derivative thereof (eg, glycine).
In some embodiments, coupling the polymer with the plurality of L-D parts causes the formation of a plurality of amide bonds.
In certain cases, the CDPs are random copolymers, in which the different subunits and / or other monomeric subunits are distributed randomly throughout the polymer chain. In this way, the formula Xm-Yn-ZQ appears, when X, Y and Z are subunits of polymers, these subunits can be randomly intercalated throughout the polymer structure. In part, the term "random" is intended to refer to the situation in which the particular distribution or incorporation of monomer units in a polymer having more than one type of monomer units is not directly directed or controlled by the synthetic protocol, but, instead, it is the result of characteristics inherent to the polymer system, such as reactivity, amounts of subunits and other characteristics of the synthetic reaction or other methods of manufacture, processing or treatment.
Pharmaceutical Compositions In another aspect, the present invention provides a composition, for example, a pharmaceutical composition, comprising a conjugate or particle of the topoisomerase inhibitor bound to CDP and a pharmaceutically acceptable carrier or adjuvant.
In some embodiments, a pharmaceutical composition can include a pharmaceutically acceptable salt of a compound described herein, for example, a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP. The pharmaceutically acceptable salts of the compounds described herein include those derived from pharmaceutically acceptable organic and inorganic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecyl sulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, rialsonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate and undecanoate. Salts derived from suitable bases include alkali metal (eg, sodium), alkaline earth metal (eg, magnesium), ammonium and N- (alkyl) 4+ salts. The present invention also provides for the quaternization of any basic nitrogen-containing group of the compounds described herein. By means of said quaternization, water or soluble or dispersible oil products can be obtained.
Wetting, emulsifying and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the compositions.
Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
A composition may include a liquid used to suspend a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, which may be any liquid solution compatible with the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, which is suitable also for use in pharmaceutical compositions, such as a non-toxic pharmaceutically acceptable liquid. Suitable suspension liquids include, but are not limited to, suspension liquids which are selected from the group consisting of water, aqueous sucrose syrups, corn syrups, sorbitol, polyethylene glycol, propylene glycol, and mixtures thereof.
A composition described herein may also include another component, such as an antioxidant, antibacterial, buffer, bulking agent, chelating agent, an inert gas, a tonicity agent and / or a viscosity agent.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is provided in lyophilized form and reconstituted prior to administration to a subject. The conjugate, particle or composition of the topoisomerase inhibitor bound to the lyophilized CDP can be reconstituted by a diluent solution, such as a salt or saline, for example, a sodium chloride solution having a pH between 6 and 9, solution of lactated Ringer's injection or a commercially available diluent, such as PLASMA-LYTE A pH 7.4® injection (Baxter, Deerfield, IL).
In one embodiment, a lyophilized formulation includes a lyoprotectant or stabilizer to maintain physical and chemical stability by protecting the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP from the damage of crystal formation and the fusion process during lyophilization. The lyoprotectant or stabilizer can be one or more of polyethylene glycol (PEG), a conjugate of PEG lipid (for example, PEG-ceramide or D-alpha-tocopheryl polyethylene glycol 1000 succinate), poly (vinyl) alcohol (PVA), poly (vinylpyrrolidone) (PVP), polyoxyethylene esters, poloxomers, Tween, lecithins, saccharides, oligosaccharides, polysaccharides and polyols (for example, trehalose, mannitol, sorbitol, lactose, sucrose, glucose and dextran), salts and ethers of coron. In one embodiment, the lyoprotectant is mannitol.
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the lyophilized CDP is reconstituted with a mixture of equal parts volume of dehydrated alcohol, USP, and a nonionic surfactant, such as a polyoxyethylated castor oil available from GAF Corporation, Mount Olive, NJ, with the brand, Cremophor EL. In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the lyophilized CDP is reconstituted in water for infusion. The lyophilized product and vehicle for reconstitution can be packaged separately in bottles adequately protected with light, for example, amber or other colored bottles. To minimize the amount of surfactant in the reconstituted solution, only a sufficient amount of the vehicle can be provided to form a solution having a concentration of about 2 mg / ml_ to about 4 mg / mL of the conjugate, particle or inhibitor composition. of the topoisomerase attached to the CDP. Once the dissolution of the drug is achieved, the resulting solution is diluted additionally before injection with a suitable parenteral diluent. Such diluents are well known to those skilled in the art. These diluents are generally available in clinical facilities. It is, however, within the scope of the present invention to package the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP in question in a third vial containing a parenteral diluent for preparing the final concentration for administration. A typical diluent is the injection of lactated Ringer.
The final dilution of the conjugate, particle or composition of the topoisomerase inhibitor bound to the reconstituted CDP can be carried out with other preparations having a similar utility, for example, 5% injection of Dextrose, Lactated Ri.nger solution and Dextrose. for Injection (D5W), Sterile Water for Injection and the like. However, given that its narrow pH range, pH 6.0 to 7.5, is the most typical Lactated Ringer injection. For every 100 mL, the injection of lactated Ringer contains sodium chloride USP 0.6 g, sodium lactate 0.31 g, potassium chloride USP 0.03 g and calcium chloride 2 H20 USP 0.02 g. The osmolarity is 275 mOsmol / L, which is very close to isotonicity.
The compositions can be conveniently presented in unit dosage forms and can be prepared by any method known in the art of pharmacy. The dosage form can be, for example, in a bag, for example, in a bag for infusion or intraperitoneal administration. The amount of active ingredient that can be combined with the carrier materials to produce a unit dosage form will depend on the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a unit dosage form in general will be the amount of compound that produces a therapeutic effect. In general, one hundred percent, this amount will vary from about 1 percent to about ninety-nine percent active ingredient, preferably from about 5 percent to about 70 percent, more preferably from about 10 percent, and approximately 30 percent.
Routes of Administration The pharmaceutical compositions described herein can be administered orally, parenterally (for example, by intravenous, subcutaneous, intracutaneous, intramuscular, intraarticular, intraarterial, intraperitoneal, intrasynovial, intrasternal, intrathecal, intransional or intracranial injection), topically, mucosally (e.g., rectally or vaginally), nasally, buccally, ophthalmically, through inhalation atomizer (e.g., administered through nebulization, propellant or a dry powder device) or through an implant reservoir. Typically, the compositions are in the form of injectable or infusible solutions. The mode of Preferred administration is, for example, intravenous, subcutaneous, intraperitoneal, intramuscular.
Pharmaceutical compositions suitable for parenteral administration comprise one or more conjugates, particles or compositions of the topoisomerase inhibitor bound to the CDP in combination with one or more sterile pharmaceutically acceptable aqueous or non-aqueous isotonic solutions or dispersions, suspensions or emulsions, or sterile powders. which can be reconstituted in sterile injectable solutions or dispersions just before use, which may contain anti-oxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and non-aqueous carriers that can be employed in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils, such as olive oil and esters. injectable organics, such as ethyl oleate. The proper fluidity can be maintained, for example, by using coating materials such as lecithin, maintaining the necessary particle size in case of dispersions and using surfactants.
These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. The prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be caused by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
In some cases, to prolong the effect of a drug, it is desirable to slow the absorption of the agent from intramuscular or subcutaneous injection. This can be done by the use of a liquid suspension of crystalline or amorphous material with low water solubility. The rate of absorption of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP depends on its rate of dissolution which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, the delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP in an oily vehicle.
Pharmaceutical formulations suitable for oral administration may be in the form of capsules, seals, pills, tablets, gums, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules or as a solution or suspension in a aqueous or non-aqueous liquid, or as a liquid emulsion of oil in water or water in oil, or as an elixir or syrup, or as a tablet (using an inert base, such as gelatin and glycerin or sucrose and acacia) and / or as mouth rinses and the like, each with a predetermined amount of an agent as an active ingredient. A compound such as a bolus, electuary or paste can also be administered.
A tablet can be used by compression or molding with one or more active ingredients. The tablets can be prepared using a binder (eg, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (eg, sodium starch glycolate or cross-linked sodium carboxymethylcellulose) .The molded tablets can be made by molding in a suitable machine a mixture of the moistened peptide or peptidomimetic powder: with an inert liquid diluent.
Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, can be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may also be formulated so as to provide a slow or controlled release of the active ingredient there using, for example, hydroxypropylmethylcellulose in various proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They can be sterilized, for example, by filtration through a bacteria retention filter or by the incorporation of sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may contain opacifying agents and may also be of a composition such that they release the vitamin D compound only or preferentially in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of inclusion compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more excipients as stated above.
The liquid dosage forms for administration! orally include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents, such as alcohol ethyl, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, peanut, corn, germ, olive, castor oil and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof.
In addition to the inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavors, colorants, perfuming agents and preservatives.
The suspensions, in addition to the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, sorbitan esters and polyoxyethylene sorbitol, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Pharmaceutical compositions suitable for topical administration are useful when the desired treatment involves easily accessible areas or organs by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with an appropriate ointment containing active components suspended or dissolved in a carrier. Carriers for topical administration of a particle described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active particle suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions described herein can also be applied topically to the lower intestinal tract by means of rectal suppository formulation or in a suitable enema formulation. Topically transdermal patches are also included herein.
The pharmaceutical compositions described herein may also be administered by nasal spray or inhalation. Such compositions are prepared according to methods well known in the pharmaceutical formulating art and can be prepared as solutions in saline, using benzyl alcohol or other preservatives or absorption promoters suitable for enhancing bioavailability, fluorocarbons and / or other solubilizing agents or dispersants known in the art.
The pharmaceutical compositions described in the present invention can also be administered in the form of suppositories for rectal or vaginal administration. The suppositories can be prepared by mixing one or more conjugates, particles or compositions of the topoisomerase inhibitor attached to the CDP described herein with one or more suitable non-irritating excipients that are solid at room temperature, but liquid at body temperature. The composition will therefore melt in the rectum or vaginal cavity and release the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP. Such materials include, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate. The compositions of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or aerosol formulations containing such carriers as are known in the art as appropriate.
Ophthalmic formulations, ointments, powders, eye solutions and the like are also contemplated as being within the scope of the invention.
Dosages and Dosing Regimes The conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP can be formulated in pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.
The actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention can be varied to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition and mode of administration, without being toxic. for the subject.
In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered at a dosage of, for example, about 1 to 40 mg / m2, about 3 to 35 mg / m2, about 9 to 40 mg / m2, for example, about 1, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mg / m2 of the topoisomerase inhibitor. Administration can occur at regular intervals, such as weekly or every 2, 3, 4, 5 or 6 weeks. Administration can occur for a period of from about 10 minutes to about 6 hours, for example, from about 30 minutes to about 2 hours, from about 45 minutes to 90 minutes, for example, about 30 minutes, minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or more. The conjugate, particle or composition of the topoisomerase inhibitor bound to CDP can be administered, for example, by intravenous or intraperitoneal administration.
In one embodiment, the conjugate, particle or composition of the topoisomerase attached to the CDP is administered as a bolus infusion or intravenous shock, for example, for a period of 15 minutes, 10 minutes, 5 minutes or less. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in such an amount that the desired dose of the agent is administered. Preferably, the dose of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is a dose described herein.
In one modality, the subject receives 1, 2, 3, up to 10 treatments or more, or even cure, heal, mitigate, alleviate, alter, remedy, alleviate, soften, improve or affect the disorder or a symptom of the disorder. For example, the subject receives an infusion every 1, 2, 3 or 4 weeks to cure, heal, mitigate, alleviate, alter, remedy, alleviate, soften, improve or affect the disorder or a symptom of the disorder. Preferably, the dosing program is a dosage program described herein.
The conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP can be administered as a first-line therapy, for example, alone or in combination with an additional agent or agents. In other embodiments, a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered after a subject has developed resistance to, has not responded to or has relapsed after a first-line therapy. The conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP can be administered in combination with a second agent. Preferably, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP can be administered in combination with a second agent described herein.
Kits A conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP described herein can be provided in a kit. The kit includes a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP described herein and, optionally, a container, a pharmaceutically acceptable carrier and / or informational material. The informational material may be descriptive, instructive, marketing or other material relating to the methods described herein and / or the use of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP for the methods described herein.
The information material of the kits is not limited in its form. In one embodiment, the informational material may include information about the production of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, physical properties of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, concentration, date of expiration, site information of the lot or production and so on. In one embodiment, the informational material refers to methods for administering the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, for example, by a route of administration described herein and / or in a dose and / or schedule. of dosage described herein.
In one embodiment, the informational material may include instructions for administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP described herein in a manner suitable for performing the methods described herein, for example, in a dosage form. of suitable dosage or mode of administration (eg, a dose, dosage form or mode of administration described herein). In another embodiment, the informational material may include instructions for administering a conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP described herein to a suitable subject, for example, a human, for example, a human suffering from or You are at risk for a disorder described here. In another embodiment, the informational material may include instructions for reconstituting a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP described herein in a pharmaceutically acceptable composition.
In one embodiment, the kit includes instructions for using the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, such as for the treatment of a subject. The instructions may include methods for reconstituting or diluting the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP for use with a particular subject or in combination with a particular chemotherapeutic agent. The instructions may also include methods for reconstituting or diluting the conjugate, particle or composition of the topoisomerase inhibitor bound to CDP for use with a particular means of administration, such as by intravenous infusion or intraperitoneal administration.
In another embodiment, the kit includes instructions for treating a subject with a particular indication, such as a particular cancer or cancer at a particular stage. For example, the instructions may be for a cancer or cancer at a stage described herein, for example, lung cancer (e.g., non-small cell lung cancer and / or small cell lung cancer, e.g., non-small cell lung cancer). squamous cells and / or small cell lung cancer) or ovarian cancer. The instructions can also be directed to the first line treatment of a subject having a particular cancer or cancer in a stage described herein. The instructions may also be directed to the treatment of a subject who did not respond to a first-line therapy or became responsive (eg, has one or more non-acceptable side effects) to a first-line therapy, such as a taxane, a anthracycline, an antimetabolite, a vinca alkaloid, an inhibitor of the vascular endothelial growth factor (VEGF) pathway, an inhibitor of the epidermal growth factor (EGF) pathway, an alkylating agent, a platinum-based agent, a vinca alkaloid. In another embodiment, the instructions will describe the treatment of selected subjects with the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP. For example, the instructions may describe the treatment of one or more of: a subject having cancer that has increasing levels of K AS and / or ST expression, for example, as compared to a reference standard.
The information material of the kits is not limited in its form. In several cases, the informational material, for example, instructions, is provided in printed material, for example, a text, drawings and / or printed photographs, for example, a label or a printed sheet. However, informational material can also be provided in other formats, such as Braille, computer-readable material, video recordings or audio recordings. In another embodiment, the information material of the kit is contact information, for example, a physical address, email address, website or telephone number, where a user of the kit can obtain substantial information about a conjugate, particle or composition of the kit. inhibitor of the topoisomerase bound to the CDP described herein and / or its use in the methods described herein. Informative material can also be provided in any combination of formats.
In addition to a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP described herein, the composition of the kit may include other ingredients, such as a surfactant, a lyoprotectant or stabilizer, an antioxidant, an antibacterial agent, a bulky agent , a chelating agent, an inert gas, a tonicity agent and / or a viscosity agent, a solvent or buffer, a stabilizer, a preservative, a flavoring agent (eg, a bitter antagonist or a sweetener), a fragrance, a dye or coloring agent, for example, for dyeing or coloring one or more components in the kit, or another cosmetic ingredient, a pharmaceutically acceptable carrier and / or a second agent for treating a condition or disorder described herein. Alternatively, the other ingredients may be included in the kit but in different compositions or packages of a conjugate, particle or composition bound to the CDP described herein. In such embodiments, the kit may include instructions for mixing a conjugate, particle or composition bound to the CDP described herein and the other ingredients or for using a conjugate, particle or composition linked to the CDP described herein together with the other ingredients. For example, the kit can include an agent that reduces or inhibits one or more symptoms of hypersensitivity, a polysaccharide and / or an agent that increases urinary excretion and / or neutralizes one or more urinary metabolites.
In another embodiment, the kit includes a second therapeutic agent, such as a second chemotherapeutic agent, e.g., a chemotherapeutic agent or combination of chemotherapeutic agents described herein. In one embodiment, the second agent is in lyophilized or liquid form. In one embodiment, the conjugate, particle or composition bound to the CDP and the second therapeutic agent are in separate containers and, in another embodiment, the conjugate, particle or composition bound to the CDP and the second therapeutic agent are packaged in the same container.
In some embodiments, a component of the kit is stored in a sealed vial, for example, with a rubber or silicone seal (eg, a polybutadiene or polyisoprene seal). In some embodiments, a component of the kit is stored under inert conditions (e.g., in nitrogen or other inert gas, such as argon). In some embodiments, a component of the kit is stored under anhydrous conditions (for example, with a desiccant). In some embodiments, a component of the kit is stored in a container that blocks light, such as a jar of amber.
A conjugate, particle or composition bound to the CDP described herein may be provided in any form, for example, liquid, frozen, dried or lyophilized form. It is preferred that a composition includes the conjugate, particle or composition, for example, a composition comprising a particle or particles including a conjugate described herein that is substantially pure and / or sterile. When a conjugate, particle or composition bound to the CDP described herein is provided in a liquid solution, the liquid solution is preferably an aqueous solution, and a sterile aqueous solution is preferred. In one embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is provided in lyophilized form and, optionally, a diluent solution is provided for the reconstitution of the lyophilized agent. The diluent may include, for example, a salt or saline, for example, a sodium chloride solution having a pH between 6 and 9, lactated Ringer's injection solution, D5W or PLASM A-LYTE injection at pH 7.4® (Baxter, Deerfield, IL).
The kit may include one or more containers for the composition containing a conjugate, particle or composition described herein. In some embodiments, the kit contains separate containers, separations or compartments for composition and informational material. For example, the composition may be contained in a bottle, bottle, IV mixing bag, IV infusion set, secondary set or syringe, and informational material may be contained in a sleeve or plastic package. In other embodiments, the separate elements of the kit are contained within a single container without divisions. For example, the composition is contained in a bottle, container or syringe that has the information material attached as a label. In some embodiments, the kit includes a plurality (e.g., a package) of individual packages, and each contains one or more unit dosage forms (e.g., a dosage form described herein) of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP described herein. For example, the kit includes a plurality of syringes, ampoules, aluminum sachets or vacuum packs, wherein each: one contains a single unit dose of a particle described herein. The packages of the kits can be hermetic, resistant to water (for example, impervious to changes in humidity or evaporation) and / or light proof.
The kit optionally includes a device suitable for the administration of the composition, for example, a jerifiga, an inhalant, a pipette, forceps, a measuring spoon, an eyedropper (e.g., an eye dropper), a cotton (e.g. , a cotton or wooden swab) or any administration device. In one embodiment, the device is a medical implant device, for example, packaged for surgical insertion.
Combination therapy The conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP can be used in combination with other known therapies. Administered "in combination", as used herein, means that two (or more) different treatments are administered to the subject during the course of the disease of) subject with the disorder, eg, two or more treatments are administered after that the subject was diagnosed with the disorder and before the disorder has been cured or eliminated or the treatment has ceased for other reasons. In some modalities, the administration of a treatment is still occurring when the administration of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as "simultaneous" or "concomitant administration". In other modalities, the administration of a treatment ends before the administration of the other treatment begins. In some modalities in any case, the treatment is more effective due to its combined administration. For example, the second treatment is more effective, for example, an equivalent effect is observed with less than the second treatment, or the second treatment reduces symptoms to a greater extent, than what would be observed if the second treatment was administered in the absence of the first treatment. treatment, or if the analogous situation is observed with the first treatment. In some embodiments, the administration is such that the reduction of a symptom, or other parameter related to the disorder, is greater than what would be observed with a treatment administered in the absence of the other. The effect of the two treatments may be partially additive, completely additive or more than additive. The administration can be such that an effect of the first administered treatment is still detectable when the second is administered.
The conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP and said at least one additional therapeutic agent can be administered simultaneously, in the same or separate compositions, or sequentially. For sequential administration, the conjugate, particle or composition of the topoisomerase inhibitor bound to CDP can be administered first, and the additional agent can be administered second, or the order of administration reversed.
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to CDP is administered in combination with other therapeutic treatment modalities including surgery, radiation, cryosurgery and / or thermotherapy. Said combination therapies may advantageously use lower dosages of the administered agent and / or other chemotherapeutic agent, thus avoiding possible toxicities or complications associated with the various monotherapies. The phrase "radiation" includes, but is not limited to, external beam therapy involving conformal and three-dimensional radiation therapy where the field of radiation is designed to conform to the volume of tissue treated; interstitial radiation therapy where seeds of radioactive compounds are implanted using ultrasound guidance; and a combination of external beam therapy and interstitial radiation therapy.
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered with at least one additional therapeutic agent, such as a chemotherapeutic agent. In certain embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with one or more chemotherapeutic agents, for example, with one or more chemotherapeutic agents described herein. Examples of classes of chemotherapeutic agents include, for example, the following: alkylating agents (including, but not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes): uracil mustard (Aminouracil Mustard®, Chlorethaminacil ®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune ™), ifosfamide (itoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte ®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylene-thiophosphoramide, Temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®) and Dacarbazine (DTIC-Dome) ®). anti-EGFR antibodies (for example, cetuximab (Erbitux®) and panitumumab (Vectibix®). anti-HER-2 antibodies (for example, trastuzumab (Herceptin®). antimetabolites (including, but not limited to, folic acid antagonists (also known herein as antifolates), pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): methotrexate (Rheumatrex®, Trexall®), 5-fluorouracil ( Adrucil®, Efudex®, Fluoroplex®), floxuridine (FUDF®), cytarabine (Cytosar-U®, Tarabine PFS), 6-mercaptopurine (Puri-Nethol®)), 6-thioguanine (Thioguanine Tabloid®), fludarabine phosphate (Fludara®), pentostatin (Nipent®), peniietrexed (Alimta®), raltitrexed (Tomudex®), cladribine (Leustatin®), clofarabine (Clofarex®, Clolar®), mercaptopurine (Puri-Nethol®), capecitabine (Xeloda®) ), nelarabine (Arranon®), aziacitidine (Vidaza®) and gemcitabine (Gemzar®). Preferred antimetabolites include, for example, 5-fluorouracil (Adrucil®, Efudex®, Fluoroplex®), floxuridine (FUDF®), capecitabine (Xeloda®), pemetrexed (Alimta®), raltitrexed (Tomudex®) and gemcitabine (Gemzar®). ). vinca alkaloids: vinblastine (Velban®, Velsar®), vincristine (Vincasar®, Oncovin®), vindesine (Eldisine®), vinorelbine (Navelbine®). platinum-based agents: carboplatin (Paraplat®, Paraplatin®), cisplatin (Platinum! ®), oxaliplatin (Eloxatin®). anthracyclines: daunorubicin (Cerubidine®, Rubidornycin®), doxorubicin (Adriamycin®), epirubicin (Ellence®), idarubicin (Idamycin®), mitoxantrone (Novantrone®), valrubicin (Valstar®). Preferred anthracyclines include daunorubicin (Cerubidine®, Rubidomycin®) and doxorubicin (Adriamycin®).
Topoisomerase inhibitors: topotecan (Hycamtin®), irinotecan (Camptosar®), etoposide (Toposar®, VePesid®), teniposide (Vumon®), lamelarin D, SN-38, camptothecin. taxanes: paclitaxel (Taxol®), docetaxel (Taxotere®), larotaxel, cabazitaxel. epothilones: ixabepilone, epothilone B, epothilone D, BMS310705, dehydelone, ZK-Epothilone (ZK-EPO). inhibitors of the poly ADP-ribose polymerase (PARP): (eg, BSI 201, Olaparib (AZD-2281), ABT-888, AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281), LT-673, 3 -aminobenzamide). antibiotics: actinomycin (Cosmegen®), bleomycin (Blenoxane®), hydroxyurea (Droxia®, Hydrea®), mitomycin (Mitozytrex®, Mutamycin®). immunomodulators: lenalidomide (Revlimid®), thalidomide (Thalomid®).
Immune cell antibodies: alemtuzamab (Campath®), gemtuzumab (Myelotarg®), rituximab (Rituxan®), tositumomab (Bexxar®). interferons (for example, IFN-alpha (Alferon®, Roferori-A®, lntron®-A) or IFN-gamma (Actimmune®)). interleukins: IL-1, IL-2 (Proleukin®), IL-24, IL-6 (Sigosix®), IL-12.
HSP90 inhibitors (for example, geldanamycin or any of its derivatives). In certain embodiments, the HSP90 inhibitor is selected from geldanamycin, 17-alkylamino-17-demethoxygelandanamycin ("17-AAG") or 17- (2-dimethylaminoethyl) amino-17-demethoxygelandanamycin ("17-DMAG"). inhibitors of angiogenesis including but not limited to, A6 (Angstrom Pharmacueticals), ABT-510 (Abbott Laboratories), ABT-627 (Atrasentan) (Abbott Laboratories / Xinlay), ABT-869 (Abbott Laboratories), Actimid (CC4047 , Pomalidomide) (Celgene Corporation), AdGVPEDF.11 D (GenVec), ADH-1 (Exherin) (Adherex Technologies), AEE788 (Novartis), AG-013736 (Axitinib) (Pfizer), AG3340 (Prinomastat) (Agouron Pharmaceuticals) , AGX1053 (AngioGenex), AGX51 (AngioGenex), ALN-VSP (ALN-VSP 02) (Alnylam Pharmaceuticals), AMG 386 (Amgen), AMG706 (Amgen), Apatinib (YN968D1) (Jiangsu Hengrui Medicine), AP23573 (Ridaforolimus / MK8669) (Ariad Pharmaceuticals), AQ4N (Novavea), ARQ 197 (ArQule), ASA404 (Novartis / Antisoma), Atiprimod (Callisto Pharmaceuticals), ATN-61 (Attenuon), AV-4 2 (Aveo Pharmaceuticals), AV-951 (Aveo Pharmaceuticals), Avastin (Bevacizumab) (Genentech) , AZD2171 (Cediranib / Recentin) (AstraZeneca), BAY 57-9352 (Telatinib) (Bayer), BEZ235 (Novartis), BIBF1120 (Boehringer Ingelheim Pharmaceuticals), BIBW 2992 (Boehringer Ingelheim Pharmaceuticals), BMS-275291 (Bristol-Myers Squibb ), BMS-582664 (Brivanib) (Bristol-Myers Squibb), BMS-690514 (Bristol-Myers Squibb), Calcitriol, CCI-779 (Torisel) (Wyeth), CDP-791 (ImClone Systems), Ceflatonin (Homoharringtonine / HHT) ) (ChemGenex Therapeutics), Celebrex (Celecoxib) (Pfizer), CEP-7055 (Cephalon / Sanofi), CHIR-265 (Chiron Corporation), NGR-TNF, GOL-3 (Metastat) (Collagenex Pharaceuticals), Combretastatin (Oxigene) , CP-751, 871 (Figitumumab) (Pfizer), CP-547,632 (Pfizer), CS-7017 (Daiichi Sankyo Pharma), CT-322 (Angiocept) (Adnexus), Curcumin, Dalteparin (Fragmin) (Pfizer), Disulfiram (Antabuse), E7820 (Eisai Limited), E7080 (Eisai Limited), EMD 121974 (Cilengitide) (EMD Pharmaceuticals), ENMD-1198 (EntreMed), ENMD-2076 (EntreMed), Endostar (Simcere), Erbitux (ImClone / Bristol-Myers Squibb), ??? - 2208 (Enzon Pharmaceuticals), EZN-2968 (Enzon Pharmaceuticals), GC1008 (Genzyme), Genistein, GSK1363089 (Foretinib) (GlaxoSmithKIine), GW786034 (Pazopanib) (GlaxoSmithKIihe), GT-111 (Vascular Biogenics Ltd.), IMC-1121B (Ramucirumab) (ImClone Systems), IMC-18F1 (ImClone Systems), IMC-3G3 (ImClone LLC), INCB007839 (Incyte Corporation), INGN 241 (Introgen Therapeutics), Iressa (ZD1839 / Gefitinib), LBH589 (Faridak / Panobinostst) (Novartis), Lucentis (Ranibizumab) (Genentech / Novartis), LY317615 (Enzastaurin) (Eli Lilly and Company), Macugen (Pegaptanib) (Pfizer), MEDI522 (Abegrin) (Medlmmune), MLN518 (Tandutinib) (Millennium), Neovastat (AE941 / Benefin) (Aeterna Zentaris), Nexavar (Bayer / Onyx), NM-3 (Genzyme Corporation), Noscapine (Cougar Biotechnology), NPl-2358 (Nereus Pharmaceuticals), OSI-930 (OSI), Palomid 529 (Paloma Pharmaceuticals, Inc.) > Panzem Capsules (2ME2) (EntreMed), Panzem NCD (2ME2) (EntreMed), PF-02341066 (Pfizer), PF-04554878 (Pfizer), PI-88 (Progen Industries / Medigen Biotechnology), PKC412 (Novartis), Polyphenon E (Green Tea Extract) (Polyphene E International, Inc.), PPI-2458 (Praecis Pharmaceuticals), PTC299 (PTC Therapeutics), PTK787 (Vatalanib) (Novartis), PXD101 (Belinostat) (CuraGen Corporation), RAD001 (Everolimus) (Novartis) ), RAF265 (Novartis), Regorafenib (BAY73-4506) (Bayer), Revlimid (Celgene), Retaane (Alcon Research), SN38 (Liposomal) (Neopharm), SNS-032 (BMS-387032) (Sunesis), SOM230 ( Pasireotide) (Novartis), Squalamine (Genaera), Suramin, Sutent (Pfizer), Tarceva (Genentech), TB-403 (Thrombogenics), Tempostatin (Collard Biopharmaceuticals), Tetrathiomólybdate (Sigma-Aldrich), TG100801 (TargeGen), Thalidomide ( Celgene Corporation), Tinzaparin Sodium, TKI258 (Novartis), TRC093 (Tracon Pharmaceuticals Inc.), VEGF Trap (Aflibercept) (Regeneron Pharmaceuticals), VEGF Trap-Eye (Regeneron Pharmaceutica ls), Veglin (VasGene Therapeutics), Bortezomib (Millennium), XL184 (Exelixis), XL647 (Exelixis), XL784 (Exelixis), XL820 (Exelixis), XL999 (Exelixis), 2D6474 (AstraZeneca), Vorinostat (Merck) and ZSTK474 . anti-androgens that include but are not limited to, nilutamide (Nilandron®) and bicalutamide (Caxodex®). antiestrogens including, but not limited to, tamoxifen (Nolvadex®), toremifene (Fareston®), letrozole (Femara®), testolactone (Teslac®), anastrozole (Arimidex®), bicalutamide (Casodex®), exemestane (Aromasin®) , flutamide (Eulexin®), fulvestrant (Faslodex®), raloxifene (Evista®, Keoxifene®) and raloxifene hydrochloride. anti-hypercalcemic agents that include but are not limited to gallium (III) nitrate hydrate (Ganite®) and pamidronate disodium (Arediá®). apoptosis inducers including, but not limited to, ethanol, 2 - [[3- (2,3-dichlorophenoxy) propyl] amino] - (9CI), gambógico acid, embelina and arsenic trioxide (Trisenox®).
Aurora kinase inhibitors that include but are not limited to, binuclein 2.
Bruton tyrosine kinase inhibitors that include but are not limited to terreic acid.
Calcineurin inhibitors that include but are not limited to cypermethrin, deltamethrin, fenvalerate and tyrphostin 8.
CaM kinase II inhibitors that include but are not limited to, 5-lsoquinolinesulfonic acid, 4-[. { 2S) -2 - [(5-isoquinolinylsulfonyl) methylamino] -3-oxo-3-. { 4-phenyl-1-piperazinyl) propyl] phenyl and benzenesulfonamide.
CD45 tyrosine phosphatase inhibitors that include but are not limited to phosphonic acid.
CDC25 phosphatase inhibitors including, but not limited to, 1,4-naphthalene dione, 2,3-bis [(2-hydroxyethyl) thio] - (9Cl).
CHK kinase inhibitors which include but are not limited to, debromohimenialdisin. cyclooxygenase inhibitors including, but not limited to, 1 H -indole-3-acetamide, 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-N- (2-phenylethyl) - (9CI), 2-arylaminophenylacetic acid substituted with 5-alkyl and its derivatives (for example, celecoxib (Celebrex®), rofecoxib (Vioxx®), etoricoxib (Arcoxia®), lumiracoxib (Prexige®), vaídecoxib (Bextra®) or 5-alkyl-2-arylaminophenylacetic acid). inhibitors of cRAF kinase that include but are not limited to, 3- (3,5-dibromo-4-hydroxybenzylidene) -5-iodo-1,3-dihydro-undol-2-one and benzamide, 3- (dimethylamino) -N- [3 - [(4-hydroxybenzoyl ) amino] -4-methylphenyl] - (9CI). cyclin-dependent kinase inhibitors including, but not limited to, olomoucine and its derivatives, purvalanol B, roascovitin (Seliciclib®), indirubin, cenpaulone, purvalanol A and ndirubi-3'-monooxime. cysteine protease inhibitors including, but not limited to, 4-morpholinecarboxamide, N - [(1 S) -3-fluoro-2-oxo-1- (2-phenylethyl) propyl] amino] -2-oxo-1- (phenylmethyl) ethyl] - (9Cl).
DNA interceptors that include but are not limited to, plicamycin (Mithracin®) and daptomycin (Cubicin®).
DNA chain destroyers that include but are not limited to bleomycin (Blenoxane®).
E3 ligase inhibitors including, but not limited to, N - ((3,3,3-trifluoro-2-trifluoromethyl) propionyl) sulfanilamide.
EGF pathway inhibitors including, but not limited to, tyrphostin 46, EKB-569, erlotinib (Tarceva®), gefitinib (Iressa®), lapatinib (Tykerb®) and those compounds that are described generically and specifically in WO 97 / 02266, EP 0 564409, WO 99/03854, EP 0 520 722, EP 0 566 226, EP 0 787 722, EP 0 837 063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and WO 96/33980.
Farnesyltransferase inhibitors including but not limited to, A-hydroxyfennesylphosphonic acid, butanoic acid, 2 - [(2S) -2 - [[(2S, 3S) -2 - [[(2R) -2-amino-3- mercaptopropyl] amino] -3-methylpentyl] oxy] -1-oxo-3-phenylpropyl] amino] -4- (methylsulfonyl) -1-methylethyl ester (2S) - (9CI) and manumicyn A.
Flk-1 kinase inhibitors that include but are not limited to, 2-propene mida, 2-cyano-3- [4-hydroxy-3,5-bis (1-methylethyl) phenyl] -N ^ (3-phenylpropyl) - (2E) - (9CI). glycogen synthase kinase inhibitors (GSK3) which include but are not limited to, indirubin-3'-monooxime. histone deacetylase inhibitors (HDAC) including, but not limited to, suberoylanilide hydroxamic acid (SAHA), [4- (2-amino-phenylcarbamoyl) -benzyl] -carbamic acid pyridine-3-ylmethyl ester and its derivatives, butyric acid , piroxamide, trichostatin A, oxamflatine, apicidin, depsipeptide, depudecin, trapoxin and compounds described in WO 02/22577. inhibitors of l-kappa kinase B-alpha (IKK) including but not limited to 2-propenenitrile, 3 - [(4-methylphenyl) sulfonyl] - (2E) - (9CI). imidazotetrazinones which include but are not limited to, temozolomide (Methazolastone®, Temodar® and its derivatives (for example, as described generically and specifically in US 5,260,291) and Mitozolomide. insulin tyrosine kinase inhibitors including, but not limited to, hydroxyl-2-naphthalenylmethylphosphonic acid. c-Jun-N-terminal kinase inhibitors (JNK) that include but are not limited to, pyrazolantrone and epigallocatechin gallate. inhibitors of mitogen-activated protein kinase (MAP) including, but not limited to, benzenesulfonamide, N- [2 - [[[3- (4-chlorophenol) -2-propenyl] methyl] amino] methyl] phenyl] -N- (2-hydroxyethyl) -4-methoxy- (9CI).
MDM2 inhibitors that include but are not limited to, trans-4-iodo, 4'-boranyl-chalcone.
MEK inhibitors including but not limited to, butanedinitrile, bis [amino [2-aminophenyl) thio] methylene] - (9CI).
MMP inhibitors which include but are not limited to, Actinonin, epigallocatechin gallate, peptidomimetic and non-peptidomimetic inhibitors of collagen, derivatives of tetracycline marimastat (Marimastat®), prinomastat, inciclinide (Metastat®), shark cartilage extract AE-941 (Neovastat®), Tanomastat, TAA211, MI270B or AAJ996. mTor inhibitors including but not limited to, rapamycin (Rapamune®), and analogs and derivatives thereof, AP23573 (also known as ridaforolimus, deforolimus or K-8669), CCI-779 (also known as temsirolimus) (Torisel ®) and SDZ-RAD.
NGFR tyrosine kinase inhibitors including, but not limited to, tyrphostin AG 879. p38 MAP kinase inhibitors including but not limited to, Phenol, 4- [4- (4-fluorophenyl) -5- (4-pyridinyl) -1 H -imidazol-2-yl] - (9CI) and benzamide, 3- (dimethylamino) -N- [3 - [(4-hydroxylbenzoyl) amino] -4-methylphenyl] - (9Cl). p56 tyrosine kinase inhibitors that include but are not limited to, damnacanthal and tyrphostin 46.
PDGF pathway inhibitors including but not limited to, tyrphostin AG 1296, tyrphostin 9, 1,3-butadiene-1, 1,3-tricarbonitrile, 2-amino-4- (1 H -indol-5-yl) - (9CI), matinib (Gleevec®) and gefitinib (Iressa®) and those compounds described generically and specifically in European Patent No. 0 564 409 and Publication PCT No .: WO 99/03854.
Phosphatidylinositol 3-kinase inhibitors including but not limited to, wortmanin and quercetin dihydrate. phosphatase inhibitors which include but are not limited to, cantharidic acid, cantharidin and L-leucinamide. protein phosphatase inhibitors including but not limited to, cantharidic acid, cantharidin, LP-bromotetramisole oxalate, 2 (5H) -furanone, 4-hydroxy-5- (hydroxymethyl) -3- (1 -oxohexadecyl) - (5R) ) - (9CI) and benzylphosphonic acid.
PKC inhibitors including but not limited to, 1-H-pyrolo-2,5-dione, 3- [1- [3- (dimethylamino) propyl] -1H-indol-3-yl] -4- ( 1 H-indol-3-yl) - (9CI), Bisindolylmaleimide IX, Sphingosine, staurosporine and Hypericin. inhibitors of PKC delta kinase including but not limited to, rotlerin. polyamine synthesis inhibitors that include but are not limited to, DMFO. proteasome inhibitors including but not limited to, aclacinomycin A, gliotoxin and bortezomib (Velcade®).
PTP1B inhibitors including but not limited to, L-leucinamide. tyrosine kinase protein inhibitors which include but are not limited to tyrphostin Ag 216, tyrphostin Ag 1288, tyrphostin Ag 1295, geldanamycin, genistein and 7 H -pyrolo [2,3-d] pyrimidine derivatives of the formula I as described generically and Specifically in PCT Publication No .: WO 03/013541 and US Publication No .: 2008/0139587: Publication No .: 2008/0139587 describes the various substituents, for example, R- ?, R2, etc. tyrosine kinase inhibitors of the SRC family including but not limited to, PP1 and PP2.
Syk tyrosine kinase inhibitors that include more. they are not limited to piceatanol.
Janus inhibitors (JAK-2 and / or JAK-3) tyrosine kinase including but not limited to tyrphostin AG 490 and 2-naphthyl vinyl ketone. retinoids including, but not limited to, isotretinoin (Accutane®, Amnesteem®, Cistane®, Claravis®, Sotret®) and tretinoin (Aberel®, Aknoten®, Avita®, Renova®, Retin-A®, Retin-A MICRO ®, Vesanoid®).
RNA polymerase II elongation inhibitors including but not limited to 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole. serine / threonine kinase inhibitors including but not limited to, 2-aminopurine. sterol biosynthesis inhibitors including, but not limited to, squalene epoxidase and CYP2D6.
VEGF pathway inhibitors including, but not limited to, anti-VEGF antibodies, eg, bevacizumab, and small molecules, eg, sunitinib (Sutent®), sorafinib (Néxavar®), ZD6474 (also known as vandetanib) (Zactima ™), SU6668, CP-547632, AV-951 (tivozanib) and AZD2171 (also known as cediranib) (Recentín ™).
Examples of chemotherapeutic agents are also described in the scientific and patent literature, see, for example, Bulinski (1997) J. Cell Sci. 110: 3055-3064; Panda (1997) Proc. Nati Acad. Sci. USA 94: 10560-10564; Muhlradt (1997) Cancer Res. 57: 3344-3346; Nicolaou (1997) Nature 387: 268-272; Vasquez (1997) Mol. Biol. Cell. 8: 973-985; Panda (1996) J. Biol. Chem 271: 29807-29812.
In some embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in place of another topoisomerase inhibitor, for example, in place of a topoisomerase inhibitor as a first-line therapy or a therapy of second line. For example, the conjugate, particle or composition of the topoisomerase inhibitor bound to CDP can be used in place of the following topoisomerase inhibitors: a topoisomerase I inhibitor, eg, camptothecin, rinotecan, SN-38, topotecan , lameralin D; an inhibitor of topoisomerase II, for example, etoposide, tenoposide, doxorubicin.
In some cases, a hormone and / or a steroid may be administered in combination with a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP. Examples of hormones and steroids include: 17a-ethinylestradiol (Estinyl®, Ethinoral®, Feminone®, Orestralyn®), diethylstilbestrol (Acnestrol®, Cyren A®, Deladumone®, Diastyl®, Domestrol®, Estrobene®, Estrobene®, Estrosyn ®, Fonatol®, Makarol®, Milestrol®, Milestrol®, Neo-Oestronol I®, Oestrogenine®, Oestromenin®, Oestromon®, Palestrol®, Stilbestrol®, Stilbetin®, Stilboestroform®, Stilboestrol®, Synestrin®, Synthoestrin®, Vagestrol®), testosterone (Delatestryl®, Testoderm®, Testolin®, Testostroval®, Testostroval-PA®, Testro AQ®), prednisone (Delta-Dome®, Deltasone®, Liquid Pred®, Lisacort®, Meticorten®, Orasone® , Prednicen-M®, Sk-Prednisone®, Sterapred®), Fluoxymesterone (Andro®dF®, Halodrin®, Halotestin®, Ora-Testryl®, Ultandren®), Dromostanolone propionate (Drolban®, Emdisterone®, Masterid®, Masteril®, Masteron®, Masterone®, Metholone®, Permastril®), testolactone (Teslac®), megestrolacetate (Magestin®, Maygace®, Megac e®, Megeron®, Megestat®, Megestil®, Megestin®, Nia®, Niagestin®, Ovaban®, Ovarid®, Volidan®), methylprednisolone (Depo-Medrol®, Medlone 21®, Medrol®, Meprolone®, Metrocort® , Metypred®, Solu-Medrol®, Summicort®), methyl-testosterone (Android®, Testred®, Virilon®), predpisolone (Cortalone®, Delta-Cortef®, Hydeltra®, Hydeltrasol®, Meti-derm®, Prelone® ), triamcinolone (Aristocort®), chlorotrianisene (Anisene®, Chlorotrisin®, Clorestrolo®, Clorotrisin®, Hormonisene®, Khlortrianizen®, Merbentul®, Metace®, Rianil®, Tace®, Tace-Fn®, Trianisestrol®), hydroxyprogesterone (Delalutin®, Gestiva ™), aminoglutethimide (Cytadren®, Elipten®, Orimeten®), estramustine (Emcyt®), medroxyprogesterone acetate (Provera®, Depo-Provéra®), leuprolide (Lupron®, Viadur®), flutamide (Eulexin) ®), toremifene (Fareston®) and goserelin (Zoladex®).
In certain embodiments, the conjugate, particle or composition of the topoisomerase inhibitor of CDP is administered in combination with an antimicrobial (e.g., leptomycin B).
In another embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with an agent or method to mitigate the possible side effects of the compositions of the agent, such as cystitis, hypersensitivity, diarrhea, nausea and vomiting. .
Cystitis can be mitigated with an agent that increases urinary excretion and / or neutralizes one or more urinary metabolites. For example, cystitis can be mitigated or treated with MESNA.
Diarrhea can be treated with antidiarrheal agents including, but not limited to, opioids (e.g., codeine (Codicept®, Coducept®), oxicodein, percocet, paregoric, opium tincture, diphenoxylate (Lomotil®), diflenoxine), and loperamide (Imodium AD®), bismuth subsalicylate, lanreotide, vapreotide (Sanvar®, Sanvar IR®), motiln antagonists, COX2 inhibitors (eg, celecoxib (Celebrex®), glutamine (NutreStore®), thalidomide (Synovir® , Thalomid®), traditional antidiarrheal remedies (eg, kaolin, pectin, berberine and muscarinic agents), octreotide and DPP-IV inhibitors.
The DPP-IV inhibitors employed in the present invention are described generically and specifically in PCT Publications Nos .: WO 98/19998, DE 196 16 486 A1, WO 00/34241 and WO 95/15309.
Nausea and vomiting can be treated with antiemetic agents such as dexamethasone (Aeroseb-Dex®, Alba-Dex®, Decaderm®, Decadrol®, Decadron®, Decasone®, Decaspray®, Deenar®, Deronil®, Dex-4 ®, Dexace®, Dexameth®, Dezone®, Gammacorten®, Hexadrol®, Maxidex®, Sk-Dexamethasone®), metoclopramide (Reglan®), diphenylhydramine (Benadryl®, SK-Diphenhydramine®), lorazepam (Ativan®), ondansetron (Zofran®), prochlorperazine (Bayer A 173®, Buccastem®, Capazine®, Combid®, Compazine®, Compro®, Emelent®, Emetiral®, Eskatrol®, Kronocin®, Meterazin®, Meterazin Maléate®, Meterazine®, Nipodal ®, Novan in®, Pasotomin®, Phenotil®, Stemetil®, Stemzine®, Tementil®, Temetid®, Vertigon®), tiethylperazine (Norzine®, Torecan®) and dronebinol (Marinol®).
In some embodiments, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with an immunosuppressive agent. Suitable immunosuppressive agents for the combination include, but are not limited to, natalizumab (Tysabri®), azathioprine (Imuran®), mitoxantrone (Novantrone®), mycophenolate mofetil (Cellcept®), cyclosporins (eg, Cyclosporin A (Neoral®, Sandimmun®, Sandimmune®, SangCya®), cacineurin inhibitors (eg, Tacrolimus (Prograf®, Protopic®), sirolimus (Rapamune®), everolimus (Afinitor®), cyclophosphamide (Clafen®, Cytoxan®, Neosár®), or methotrexate (Abitrexate®, Folex®, Methotrexate®, Mexate®), fingolimod, mycophenolate mofetil (CellCept®), mycophenolic acid (Myfortic®), anti-CD3 antibody, anti-CD25 antibody (for example, Basiliximab ( Simulect®) or daclizumab (Zenapax®), and anti-TNFa antibody (eg, Infliximab (Remicade®) or adalimumab (Humira®)).
In some embodiments, a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered in combination with a CYP3A4 inhibitor (e.g., ketoconazole (Nizoral®, Xolegel®), itraconazole (Sporanox®), clarithromycin (Biaxin® ), atazanavir (Reyataz®), nefazodone (Serzone®, Nefadar®), saquinavir (Invirase®), telithromycin (Ketek®), ritonavir (Norvir®), amprenavir (also known as Agenerase, a version of the prodrug is fosam prenavir ( Lexiva®, Telzir®), indinavir (Crixivan®), nelfinavir (Viracept®), delavirdine (Rescriptor®) or voriconazole (Vfend®)).
When the methods or compositions are employed, other agents used in the modulation of tumor growth or metastasis in a clinical setting, such as antiemetics, may also be administered as desired.
When formulating the pharmaceutical compositions presented in the invention, the physician may use preferred dosages as justified by the affection of the subject being treated. For example, in one embodiment, a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP can be administered in a dosing schedule described herein, eg, once each, two, three or four weeks.
Also, in general, a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP and one or more additional chemotherapeutic agents should not be administered in the same pharmaceutical composition and may have to be administered, due to diverse physical and chemical characteristics, through different ways. For example, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP can be administered intravenously while the chemotherapeutic agent (s) can be administered orally. The determination of the mode of administration and the convenience of administration, when possible, in the same pharmaceutical composition, is within the knowledge of the skilled physician. The medical administration can be carried out according to established protocols known in the art and then, based on the observed effects, the skilled physician can modify the dosage, the modes of administration and the times of administration.
In one embodiment, a conjugate, particle or composition of the topoisomerase inhibitor bound to CDP is administered once every three weeks and an additional therapeutic agent (or additional therapeutic agents) can also be administered every three weeks while the treatment is needed. Examples of other chemotherapeutic agents that are administered once every three weeks include: an antimetabolite (e.g., floxuridine (FUDF®), pemetrexed (ALIMTA®), 5FU (Adrucil®, Efudex®, Fluoroplex®)); an anthracycline (e.g., daunorubicin (Cerubidine®, Rubidomycin®), epirubicin (Ellence®), idarubicin (Idamycin®), mitoxantrone (Novantrone®), valrubicin (Valstar®)); a vinca alkaloid (for example, vinblastine (Velban®, Velsar®), vincristine (Vincasar®, Oncovin®), vindesine (Eldisine®) and vinorelbine (Navelbine®)); a taxane (for example, paclitaxel, docetaxel, larotaxel and cabazitaxel); and a platinum-based agent (e.g., cisplatin (Platinol®), carboplatin (Paraplat®, Paraplatin®), oxaliplatin (Eloxatin®)).
In another embodiment, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP is administered once every two weeks in combination with one or more additional chemotherapeutic agents that are administered orally. For example, the conjugate, particle or composition of the topoisomerase inhibitor bound to CDP can be administered once every two weeks in combination with one or more of the following chemotherapeutic agents: capecitabine (Xeloda®), estramustine (Emcyt®), erlotinib (Tarceva®), rapamycin (Rapamune®), SDZ-RAD, CP-547632; AZD2171, sunitinib (Sutent®), sorafenib (Nexavar®) and everolimus (Afinitor®).
The actual dosage of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP and / or any chemotherapeutic agent employed may vary depending on the requirements of the subject and the severity of the condition being treated. The determination of the proper dosage for a particular situation is within the skill of the art. In general, treatment starts with lower dosages that are less than the optimum dose of the compound. Then, the dosage is increased in small amounts until the optimum effect is achieved under the circumstances.
In some embodiments, when a conjugate, particle or composition of the topoisomerase inhibitor bound to CDP is administered in combination with one or more additional chemotherapeutic agents, the additional chemotherapeutic agent (s) is administered at a standard dose. For example, a standard dosage for cisplatin is 75-120 mg / m2 administered every three weeks; a standard dosage for carboplatin is within the range of 200-600 mg / m2 or an AUC of 0.5-8 mg / ml x min; for example, in an AUC of 4-6 mg / ml x min; a standard dosage for irinotecan is found within 100-125 mg / m2, once a week; a standard dosage for gemcitabine is within the range of 80-1500 mg / m2 administered weekly; A standard dose for UFT is within a range of 300-400 mg / m2 per day when combined with the administration of leucovorin; A standard dosage for leucovorin is 10-600 mg / m2 administered weekly.
The description also encompasses a method for the synergistic treatment of cancer where a conjugate, particle or composition of the topoisomerase inhibitor bound to CDP is administered in combination with an additional chemotherapeutic agent or agents.
The particular choice of the conjugate, particle or composition and anti-proliferative cytotoxic agent (s) or radiation will depend on the diagnosis of the treating physicians and their judgment on the subject's condition and the appropriate treatment protocol.
If the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP and the chemotherapeutic agent (s) and / or radiation are not simultaneously or simultaneously administered in an essential manner, then the initial order of administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP and the chemotherapeutic agent (s) and / or radiation may vary. Thus, for example, the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP can be administered first after the administration of the chemotherapeutic agent (s) and / or radiation; or the chemotherapeutic agent (s) and / or radiation can be administered first after the administration of the conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP. This alternative administration can be repeated during a single protocol of treatment. The determination of the order of administration and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is within the knowledge of the expert physician after the evaluation of the disease being treated and the affection of the subject.
Therefore, according to experience and knowledge, the medical practitioner can modify each protocol for the administration of a component (conjugate, particle or composition of topoisomerase inhibitor bound to CDP, anti-neoplastic agent / s or radiation). ) of the treatment according to the individual needs of the subject, while the treatment proceeds.
The treating physician, judging whether the treatment is effective in the dosage administered, will consider the general well-being of the subject as well as more defined signs, such as relief of symptoms related to the disease, inhibition of tumor growth, actual shrinkage of the tumor or inhibition of the tumor. metastasis. The size of the tumor can be measured by standard methods, such as radiological studies, for example, CAT or MRI tomography, and successive measurements can be used to judge whether tumor growth was delayed or even reversed or not. The relief of symptoms related to the disease, such as pain, and the improvement in the general condition can also be used to help judge the effectiveness of the treatment.
Indications The conjugates, particles and compositions of the topoisomerase inhibitor bound to the CDP are useful for the treatment of proliferative disorders, for example, treatment of a tumor, eg, a primary tumor and / or metastasis thereof, where the tumor is a tumor primary or a metastasis thereof, for example, a cancer described herein or a metastasis of a cancer described herein.
The methods described herein can be used to treat a solid tumor, a soft tissue tumor or a liquid tumor. Examples of solid tumors include neoplasms (e.g., sarcomas and carcinomas (e.g., adenocarcinoma or squamous cell carcinoma)) of the various organ systems, such as brain, lung, breast, lymphoid, gastrointestinal (e.g. colon) and genitourinary tracts (for example, renal, urothelial or testicular tumors), pharynx, prostate and ovary. Examples of adenocarcinomas include colorectal cancers, renal cell carcinoma, liver cancer, non-small cell lung carcinoma, and small bowel cancer. The described methods are also useful for the evaluation or treatment of soft tissue tumors such as those of tendons, muscles or fat and liquid tumors.
The methods described herein can be used with any cancer, for example those described by the National Cancer Institute. The cancer can be a carcinoma, a sarcoma, a myeloma, a leukemia, a lymphoma or a mixed type. Examples of cancers described by the National Cancer Institute include: Gastrointestinal / digestive cancers such as, anal cancer; cancer of the bile ducts; cancer of the extrahepatic bile ducts; appendix cancer; carcinoid tumor, gastrointestinal cancer; colon cancer; colorectal cancer including colorectal cancer in children; esophageal cancer including esophageal cancer in children; gallbladder cancer; Gastric cancer (stomach) including gastric (stomach) cancer in children; hepatocellular cancer (liver) including hepatocellular cancer (liver) in children; pancreatic cancer including pancreatic cancer in children; sarcoma, rhabdomyosarcoma; pancreatic cancer, islet cell; rectal cancer and small bowel cancer; Endocrine cancers such as, islet cell carcinoma (endocrine pancreas); Adrenocortical carcinoma including adrenocortical carcinoma in children; Gastrointestinal carcinoid tumor; parathyroid cancer; pheochromocytoma; pituitary tumor; thyroid cancer including thyroid cancer in children; multiple endocrine neoplasia syndrome in children and carcinoid tumor in children; Cancers in the eye such as, intraocular melanoma and retinoblastoma; Musculoskeletal cancers such as, Ewing's family of tumors; osteosarcoma / bone malignant fibrous histiocytoma; rhabdomyosarcoma including rhabdomyosarcoma in children; soft tissue sarcoma including soft tissue sarcoma in children; sarcoma of clear cells of the tendon sheath and uterine sarcoma; Breast cancer such as, breast cancer and pregnancy including breast cancer in men and boys; Neurological cancers such as brain stem glioma in children; brain tumor; cerebellar astrocytoma in children; cerebellar astrocytoma / malignant glioma in children; ependymoma in children; medulloblastoma in children; primitive pineal and supratentorial neuroectodermal tumors in children; hypothalamic glioma and optic tract in children; other brain cancers in children; adrenocortical carcinoma; lymphoma of the central nervous system, primary; cerebellar astrocytoma in children; neuroblastoma; Craniopharyngioma; spinal cord tumors; rhabdoid tumor / atypical teratoid of the central nervous system; embryonal tumors of the central nervous system and primitive supratentorial neuroectodermal tumors including pituitary tumor and in children; Genitourinary cancers such as, bladder cancer including bladder cancer in children; renal cell cancer (kidney); ovarian cancer including ovarian cancer in children; epithelial cancer of the ovaries; ovarian tumor of low malignant potential; penis cancer; prostate cancer; renal cell cancer including renal cell cancer in children; cancer of transitional cells of the renal pelvis and of the ureter; Testicular cancer; urethral cancer; vaginal cancer; vulvar cancer; cervical cancer; Wilms tumor and other kidney tumors in children; endometrial cancer and gestational trophoblastic tumor; Germ cell cancers such as, extracranial germ cell tumor; extragonadal germ cell tumor; germ cell tumor of the ovary and testicular cancer; Head and neck cancers such as, cancer of the lip and oral cavity; oral cancer in children; cancer of the hypopharynx; cancer of the larynx including cancer of the larynx in children; squamous metastatic cancer of the neck with occult primary tumor; mouth cancer; cancer of the paranasal sinus and the nasal cavity; cancer of the nasopharynx including cancer of the nasopharynx in children; cancer of the oropharynx; parathyroid cancer; cancer of the pharynx; cancer of the salivary gland including cancer of the salivary gland in children; throat cancer and thyroid cancer; Blood / hematological cell cancers such as, a leukemia (e.g., acute lymphoblastic leukemia in adults and children; acute myeloid leukemia, e.g., in adults and children; chronic lymphocytic leukemia; chronic myelogenous leukemia and hairy cell leukemia); a lymphoma (e.g., AIDS-related lymphoma; cutaneous T-cell lymphoma; Hodgkin's lymphoma including Hodgkin's lymphoma in adults and children; Hodgkin's lymphoma during pregnancy; non-Hodgkin's lymphoma including non-Hodgkin's lymphoma in adults and children non-Hodgkin's lymphoma during pregnancy, mycosis fungoides, Sézary syndrome, Waldenstrom's macroglobulinemia, and primary central nervous system lymphoma); and other hematologic cancers (eg, chronic myeloproliferative disorders, multiple myeloma / plasma cell neoplasm, myelodysplastic syndromes, and myelodysplastic / myeloprol iterative disorders); Lung cancer such as, non-small cell lung cancer and small cell lung cancer; Respiratory cancers such as, malignant mesothelioma including malignant mesothelioma in adults and children; myalignan thymoma; thymoma in children; thymic carcinoma; bronchial adenomas / carcinoids including bronchial adenomas / carcinoids in children; pleuropulmonary blastoma; non-small cell lung cancer and small cell lung cancer; Skin cancers such as Kaposi's sarcoma; Merkel cell carcinoma; melanoma and skin cancer in children; Neoplasms related to AIDS; Other cancers in children, cancers not usual in children and cancers of unknown primary site and metastases of the cancers mentioned above can also be treated or prevented according to the methods described herein.
The conjugates, particles and compositions of the topoisomerase inhibitor bound to CDP described herein are particularly suitable for treating accelerated or metastatic cancers of gastric cancer, colorectal cancer, non-small cell lung cancer, ovarian cancer and breast cancer.
In one embodiment, a method for a combination treatment of a cancer is provided, such as by treatment with a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP and a second therapeutic agent. Various combinations are described herein. The combination can reduce the development of tumors, reduce the volume of the tumor or produce regression of the tumor in a mammalian host.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which the present invention pertains. All publications, patent applications, patents and other references mentioned herein are incorporated by this reference in their entireties. In case of conflict, the present descriptive memory will prevail, including the definitions. Also, the materials, methods and examples are illustrative only and are not intended to be limiting.
Examples Example 1: Phase 1 Human Study of CRLX101 The example below describes the first phase 1 human study of CRLX101. The study was composed of two parts. Part 1 of the Phase 1 study had a primary objective to determine the safety, toxicity and pharmacokinetics profile of CRLX101 when administered weekly for 3 weeks consecutive of each 4-week cycle (the initial dosing regimen, often referred to herein as "3 times a week"). In part 2, after the first twelve patients enrolled, a week-by-week program was initiated for the part of the Phase 1 program (often referred to here as "biweekly").
Patients and Methods Election Criteria For this test, patients with histologically or cytologically confirmed unresectable or metastatic tumors were resistant to standard therapy, or for whom there was no standard palliative or curative therapy. Previous treatment with topoisomerase inhibitors was allowed. The main selection criteria include male or female patients, at least 18 years of age, with solid histologically confirmed and advanced tumor resistant to standard treatment, or for which there was no standard therapy, measurable or measurable disease, state of performance of the Group Oncological Cooperative of the East (ECOG) = 2, function of bone marrow and organs acceptable, absence of ischemia test or clinically significant conduction anomalies and ejection fraction > Four. Five%. Before chemotherapy, radiation therapy or research therapy had to be completed within a prescribed range before enrollment, high-dose chemotherapy and autologous or bone marrow transplantation could not have been included. rescue of stem cells, and the patients could not have been insensitive to previous treatment with an inhibitor of topoisomerase I.
The test was carried out at the City of Hope (COH) (Duarte, CA) after the approval of the Clinical Protocol Review and Monitoring Committee (CPRMC) and the Institutional Review Board (IRB). After the initial 18 patients were enrolled, an additional site was added to TGen (Scottsdale, AZ) following the approval of the WIRB (Western Institutional Review Board).
Study Design and Drug Administration.
This was a Phase 1 study of dose increase, of a single group, of open label of CRLX101. In part 1, CRLX101 was administered at 6, 12 or 18 mg / m2 in a weekly schedule, three weeks a month. In part 2, CRLX101 was administered at 12, 15 or 18 mg / m2 in a week-by-week program.
In part 1, CRLX101 was administered as an intravenous infusion for 90 minutes on days 1, 8 and 15 followed by a rest period of 7 days (28 day cycle). In part 2, CRLX101 was administered as an intravenous infusion for 90 minutes on days 1 and 15, every 28 days. CRLX101 was administered as an intravenous infusion for 60 minutes on days 1 and 15, every 28 days for the last six patients in part 2 of the Phase 1 study.
The starting dose in part 1 was 6 mg / m2. The dose increase was performed using an accelerated Simón design (Simón et al., "Accelerated Titration Designs for Phase I Clinical Triáis in Oncology "J Nati Cancer Inst. 89: 1138-47, 1997) with a modified Fibonacci dose increase scheme In summary, patients were accumulated in cohorts of one in increasing doses until the appearance of a dose-limiting toxicity ( DLT) in the first cycle Once the DLT happened, more patients were accumulated in that dosage group to provide 3 or 6 patients as provided in a standard dose increase with the intention of determining the maximum tolerated dose. allowed concomitant increase within the same dose level No dose increase between patients was allowed.
Toxicity Evaluation.
Toxicity was classified according to the Common Toxicity Criteria (CTCAE) of the National Cancer Institute (NCI) version 3.0. DLT in a given patient was defined as any non-haematological toxicity of grade III related to treatment, any hematologic toxicity of grade IV or persistent toxicities of any degree requiring delayed treatment scheduled for more than 2 weeks. The DLT was based on the first part of the treatment.
Rules for Increasing Dose.
A patient was treated at each dose level. If a DLT attributable to the study drug (s) was experienced, up to 5 additional patients were subsequently treated at that dose level. If no additional DLT was observed at the expanded dose level (ie, at most 1/6 with an attributable DLT), the dose was increased. The increase ended when two of six patients experienced any DLT attributable to the study drug at a given dose level. The maximum tolerated dose (MTD) was defined as the dose level preceding the dose in which = 2/6 patients experienced a DLT in the first part. Treatment was continued in an individual patient for a total of 6 cycles at the same dose level in the case in which DLT was not observed and clinical benefit was observed. The therapy was discontinued in any patient in the case of experiencing excessive toxicity. No dose increase between patients was allowed. Patients who completed 6 cycles with clinical benefit had the option of continuing treatment at the same dose level week by week.
Safety and Efficacy Assessments.
The patients were observed and examined and a complete blood count was obtained with serum chemistry and differential before each dose. Radiographic evaluations of tumor response (as evaluated by the RECIST solid tumor response evaluation criteria) were performed every two cycles (Therasse et al., "New Guidelines to Evaluate the Response to Treatment in Solid Tumors." European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada "J. Nati. Cancer Inst. 92: 205-16, 2000).
Modification of the Treatment.
To patients who experienced a DLT during the initial cycle, or a life-threatening or serious non-haematological toxicity at any time during the study, the dose was reduced at the next dose administration when their DLT returned to Grade 1. If a non-haematological DLT occurred in the interval between administrations of the dose within a cycle, and the toxicity did not threaten life and was quickly resolved, the next dose administration within the cycle had to occur at the next lower dose level. If a haematological DLT occurred in the interval between dose administrations within a cycle, the next dose administration was to occur at the next lower dose level, even if the cell counts were recovered at the next date scheduled administration. The dosage should be made for any degree of non-haematological toxicity >; 2, except for fatigue and grade 2 anorexia. After the first cycle, the modifications were based on interval toxicity, and platelet and granulocyte counts were obtained on the day of treatment.
Hematological toxicity: On day 1 of a cycle, administration of CRLX101 required an absolute granulocyte count (AGC) of > 1500 and platelet count of > 100,000 On day 8, if the AGC was > 1000 and the platelet count > 75,000, then CRLX101 was given in a full dose and in the same way for day 15. If the AGC was < 1000, then treating physicians could delay the dose of CRLX101 on days 8 and 15. If persistent hematological toxicity persisted > 7 days, the dose of CRLX101 was reduced to the next lower dose level. Similar standards were used in the biweekly part.
Non-Hematological Toxicity: Any grade 2 toxicity that was intolerable to patients, or any grade 3 or higher non-haematological toxicity that was attributable to CRLX101, had to return to grade 1 before a new treatment cycle was started. Any delay in treatment > 2 weeks for toxicity due to CRLX101 would cause the patient to withdraw from the study. If a patient experienced any genito-urinary toxicity (GU) of grade 3, the dose of CRLX101 was reduced to the next lower dose level, as reported by the CPT that causes hematuria, cystitis, or other GU toxicities, which may be irreversible. If the patient experienced non-haematological grade 3 toxicities that did not recover to grade 1 before the next treatment, treatment was maintained until recovery and then reduced at a dose level. If the patient experienced grade 4 non-hematologic toxicities that did not recover to grade 1 before the next treatment, then the dose was reduced by 50% in subsequent cycles. If there were attenuations of conflicting doses due to haematological and non-haematological toxicity, greater dose reduction was applied. All modifications to the doses were permanent. Criteria for withdrawal from treatment included progression of the disease, clinical progression, excessive toxicity, or withdrawal of the patient.
Sampling and Analysis of Plasma / Urine.
Blood samples (5 ml_) were collected in heparinized tubes at the following times during cycle one: before the dose, during dosing at 30 minutes, 60 minutes and just before the end of administration (90 minutes), and then to 0.25, 0.5, 1, 2, 3, 4, 6, 8, 24, (48-72 hr optional), 168 hours (1 week), and 336 hours (only for patients in a biweekly program) after the first dose. A random minimum PK blood sample was collected before dosing on day 1 and day 15 of each cycle. The plasma was separated by centrifugation at 1,300 x g for 10 minutes at 4 ° C. The plasma was frozen immediately at -20 ° C and stored frozen until analysis. For the determination of urinary excretion of unbound and conjugated CPT with the polymer, total urine collections were carried out after dose 1 of the first cycle (0-24 and 24-48 hours after administration). A random urine sample (15 mL) was collected at 8, 24, 48, 168 (1 week) and 336 hours (before the second dose) for a more accurate determination of the total to release the CPT ratio. Once the urine collection was completed, the actual collection and total volume of urine were recorded and aliquots of 5-10 mL of each were frozen for subsequent drug level analysis.
The samples were extracted and analyzed by LC-MS / MS (liquid chromatography-mass spectrometry / mass spectrometry) using a validated method. To determine the total CPT in samples, an aliquot of 20μ? Was incubated with 5μ? _ Of 0.2N NaOH for 1 hour to release the entire CPT of the polymer conjugate. The solution was acidified with 7 pL of 44% formic acid. The proteins were precipitated by the addition of 160 pL of cold methanol (<-20 ° C) containing the 9-nitro internal standard camptothecin (9-NC) at a concentration of 8 ng / mL, incubation for 30 minutes on ice and centrifugation at 14,000 rpm. The resulting supernatant was diluted with an equal volume of 0.5 mM ammonium acetate buffer, pH 3.5, and analyzed by LC-MS / M! S.
To determine the unconjugated CPT in samples, an aliquot of 20pL was acidified with 3 pL of 44% formic acid. The proteins were precipitated by the addition of 160 pL of cold methanol (<-20 ° C) containing 9-NC in a concentration of 8 ng / mL, incubation for 30 minutes on ice and centrifugation at 14,000 rpm. The resulting supernatant was diluted with an equal volume of 0.5 mM ammonium acetate buffer, pH 3.5 and analyzed by LC-MS / MS.
LC-MS / MS was carried out in an Agilent 1100 series HPLC system (Palo Alto, CA) coupled to a Micromass Quattro Ultima mass spectrometer with triple quadrupole (Micromass, Inc., Beverly, MA). HPLC separation was achieved using an analytical column of Synergy Hydro-RP 4pm 75 x 2 mm (Phenomenex, Torrance, CA) preceded by a protection column d8 (Phenomenex, Torrance, CA). The mobile Socratic phase consisted of 34% acetonitrile, 0.5 mM 66% ammonium acetate, pH 3.5 at a flow rate of 0.2 mL / min at room temperature. MassLynx version 3.5 software was used for data processing and acquisition.
Immunohistochemical Analysis of Topoisomerase Expression L The ascites fluid from a patient with ovarian cancer was obtained before treatment and the second day after treatment with CRLX101 at 6 mg / m2. The cells were pelleted by centrifugation and the pellet was frozen. The sediment was fixed with formalin and embedded with paraffin. Immunohistochemical staining was performed in 5 μm thick sections. Sections were deparaffinized in xylene followed by 100% ethanol. The samples were then inactivated in 3% hydrogen peroxide and pretreated to promote antigen recovery by DIVA solution / citrate buffer vapor (pH 6.0, Biocare Medical, Concord, CA). After recovery of antigens, the slides were incubated in protein block for 20 minutes. The sheets were then incubated with the main antibody overnight at 4 ° C. The topoisomerase I antibody was polyclonal rabbit from Abcam (Cambridge, MA).
The next day, the plates were washed in Dako buffer (DB) and incubated with the appropriate secondary antibodies for 30 minutes at room temperature. After washing in DB, the sheets were incubated with chromogenic diaminobenzidine tetrachlorohydrate (DAB), counterstained with hematoxylin, and mounted.
Topoisomerase I Enzymatic Activity Test I.
The Used ones that contained the total cellular protein were made from frozen natural ascites cells according to the method of Minagawa et al. ("Enhanced Topoisomerase I Activity and Increased Topoisomerase II Alpha Contained in Cisplatin-Resistant Cancer Cell Lines" Jpn J Cancer Res. 88: 1218-23, 1997), a procedure used specifically for frozen cells.
The catalytic activity of topoisomerase I was determined by measuring the relaxation of the superhelical plasmid DNA substrate using the Topo I assay kit (TopoGEN, Port Orange, FL) following the manufacturer's instructions. Briefly, the reaction mixtures consisted of superhelical plasmid DNA substrate (0.5 pg), whole cell lysate (0.25 pg or 0.5 pg, as indicated in the data) and the assay buffer (final concentrations: 10 mM HCI Tris [pH 7.9], 1 mM EDTA, 150 mM NaCl, 0.1% BSA, 0.1 mM spermidine and 5% glycerol). The reaction mixtures were incubated at 37 ° C for 30 minutes and finalized by the addition of 5 pL of stop buffer / gel charge buffer. Samples were loaded on a 1% agarose gel in 1x TAE buffer (40 mM of Tris base [pH 8.3, adjusted in 50 x buffer using acid glacial acetic acid], 2.5 mM NaOAc and 0.05 m EDTA) and electrophoresed at 4-5 volts per centimeter for 3-4 hours. The superhelical plasmid DNA (0.5 pg) and relaxed DNA (0.5 pg) provided by the Topo I assay kit were used as the control markers. The gel was stained with 0.2 pg / mL of ethidium bromide for 20 minutes at room temperature, destained in water for 20 minutes and photographed in ultraviolet (UV) light.
Pharmacokinetic and Statistical Analysis.
The plasma concentration versus time data were analyzed using the non-compartmental model ADAPT II (Biomedical Simulations Resource, Los Angeles). The results are summarized using descriptive statistics.
Results Patient Registration.
Twenty-four patients were enrolled from June 2006 to April 2010. Patient characteristics are summarized in Table 1. Patients had a variety of solid tumors, with lung cancer being the most common type of tumor. The twenty-four patients were considered evaluable for toxicity having received two complete cycles of therapy.
Table 1. Patient demographics Tumor response.
The data and dosage of the patient are shown in Table 2. In the first-dose program (part 1), a patient with metastatic pancreatic cancer that expanded to lungs and liver experienced stable disease and received coinpassive treatment for a total of 22 cycles before the progression of the disease. The results of a CT scan performed on this patient are shown in FIGS. 1A and 1B. Four patients experienced prolonged SD (stable disease) (> 6 months), one patient with renal cancer with metastases in the lung, two patients with non-small cell lung cancer and one patient with adenocarcinoma of the pancreas. (Table 3). All patients had been heavily pitted for metastatic disease (see Table 3).
Although the protocol allowed prior treatment with CPT, none of these patients had received treatment with previous CPT.
Table 2. Population analysis and patient disposition. 5 Note: A patient still active - currently in cycle 5.
Four patients who completed 6 cycles of therapy continued to receive CRLX101 week in a compassionate use basis. Abbreviations: AE = adverse event, SD = stable disease, PD = progressive disease, DR = related drug, Pt = patient Table 3. CRLX101 showed activity in this population of heavily pretreated patients with progression-free survivors of 4 long periods, two of whom showed minor responses.
Abbreviations: PFS = progression-free survival, SD = stable disease Toxicity Evaluation.
All patients of the first twelve enrolled (3 times a week) experienced grade 3 or 4 toxicities at doses above 6 mg / m2. The program 3 times a week was stopped after these first twelve patients due to the severe toxicity observed in all patients treated in doses higher than 6 mg / m2. One patient tolerated 9 mg / m2 in a program of 3 times a week for five cycles (three doses per cycle).
No patient of the second 12 patients enrolled in the biweekly program experienced severe toxicity until BAT was achieved. The DLT of grade 2 included the following.
A patient with bladder cancer experienced grade 2 anemia in cycle 2, day 8. This grade 2 hematologic toxicity resolved in two weeks.
A patient with lung cancer experienced elevated amylase in laboratory tests but had no clinical manifestation of pancreatitis.
A patient with head and neck cancer (nasopharyngeal cancer with significant prior chemotherapy) experienced transam initis grade 2 with delayed onset in cycle 2, day 1.
A patient with lung cancer experienced grade 2 hematologic toxicity that resolved in two weeks.
At the highest dose tested, two patients experienced hematologic toxicities of DLT. The first patient, a patient with breast cancer, who had metastatic disease to the lung and other organs and who previously received several chemotherapy regimens, developed grade 3 anemia, neutropenia and thrombocytopenia. This patient needed platelet transfusions. The second patient had metastatic lung cancer and had previously received carboplatin and paclitaxel with a brief response. This patient developed grade 3 neutropenia, which requires a dose reduction and support of the granulocyte colony stimulating factor (G-CSF). This haematological toxicity in 2 of 3 patients established 18 mg / m2 as the level of DLT.
A patient with pancreatic cancer experienced grade 2 anemia in cycle 5, day 1.
A patient with hepatocellular cancer died one week after cycle 3, day 1, due to progressive disease.
A patient with lung cancer who had received several previous regimens developed grade 2 neutropenia in cycle 3, day 15. This patient needed a reduction in the dose and support of G-CSF.
Based on the durable terminal half-life of the conjugated CPT, and especially non-conjugated CPT, with the polymer (see FIGS 2A and 2B), the protocol was corrected in part 2 to evaluate a week-by-week schedule. A total of 12 patients were treated in this program, three with 12mg / m2 and six with 15 mg / m2 and three with 18mg / m2. With the exception of one occurrence of grade 3 neutropenia, there were no hematological events of grade 3/4 with the dose levels of 12mg / m2 and 15mg / m2. At the 18 mg / rn2 dose level, grade 4 leukopenia, two grade 4 neutropenias, two grade 4 thrombocytopenia and grade 3 anemia were reported in haematological toxicities. This determined the DLT of bone marrow suppression at 18 mg / m2 in this program. The only observable non-hematologic additional event was a grade 3 hypersensitivity reaction (Table 4).
Table 4 shows a summary of all toxicities related to grade 3/4 treatment for all evaluable patients. Four patients in the weekly program developed mild dysuria and mild hematuria with delayed onset (after cycle 4) that may have been related to treatment as previously observed for CPT (Muggia et al., "Phase I Clinical Trial of Weekly and Daily Treatment wth Camptothecin (NSC-100880): Correlation ith Preclinical Studies "Cancer Chemother Rep 56: 515-521, 1972). However, after evaluation by a urologist, cystitis could not be confirmed. Thus, two patients who developed DLT were reported twice weekly with 18 mg / m2, and the BAT for the biweekly program was established at 15 mg / m2.
Table 4: Haematological and non-haematological adverse events of grade 3/4 related to treatment by dose cohort observed during all parts of the therapy.
Pharmacokinetic and Toxicokinetic Analysis.
Samples for pharmacokinetic analysis were collected from all patients during cycle 1. The results of this analysis are summarized in FIGS. 2A, 2B and Table 5. Mean elimination half-lives were 31.8 ± 5.7 hr and 43.8 ± 9.7 hr for conjugated and unconjugated CPT, respectively. The volume of distribution of the polymer conjugate was 4.2 ± 1.1 liters and was independent of the dose. The low volume of distribution suggests that CRLX101 is initially retained in the plasma and prevents rapid first-pass elimination. Cmx and AUC0-nf were linear at all doses and similar when normalized to dose / m2. FIGs. 2A and 2B summarize the pharmacokinetic parameters measured for the CPT conjugated and unconjugated with the polymer for both programs. The unconjugated CPT was released slowly from CRLX101 as shown by increasing plasma concentrations that had a peak at 20.2 ± 9.7 hrs. Plasma concentrations of unconjugated CPT were significantly below the plasma concentrations of conjugated CPT at all time points, with the unconjugated CPT representing an average of 8.7 ± 2.7% of total CPT plasma exposure. FIG. 2A shows average time-concentration curves of plasma for the cohort of 12 mg / m biweekly. The systemic plasma clearance of conjugated CPT was 0.12 ± 0.2 L / h, significantly below the blood flow of kidney and liver, and was also dose independent. FIG. 2B shows the average urinary excretion of CPT conjugated and unconjugated with the polymer in the first 48 hours after administration of CRLX101. The urinary loss of total CPT was variable with an average of 22.8 ± 12.1% of the dose excreted during the first 48 hours, of which 78 + 9% was in the conjugate form. Interestingly, the urinary excretion of the polymer conjugate was mainly in the first 24 hours (16.4% ± 10.0% dose) compared to the second 24 hours (1.5 ± 1.3% dose) after administration. Urinary excretion of unconjugated CPT remained approximately constant during both 24-hour periods (2.0 ± 1.1% compared to 2.9 ± 1.4% dose). The toxicocineticp analysis of the two programs showed that the predicted monthly exposure for conjugated and unconjugated CPT was similar for 6 mg / m2 weekly compared to 12 mg / m2 biweekly and 12 mg / m2 weekly compared to 15 mg / m2 biweekly. However, fewer patients experienced adverse events related to the cyclo-1 drug with the biweekly regimen.
Table 5. Pharmacokinetic parameters and toxicokinetic summary. The values are in average deviation ± geometric standard.
Correlative Studies.
The ascites cells were collected from a patient with previous treatment of ovarian cancer and on days 2 and 25 after treatment. The pellets of these cells were frozen for further analysis. The levels of CPT conjugated and unconjugated with the polymer were also determined in the ascites fluid before treatment and on day 2 after treatment. On day 2, the concentrations detected were 46.6 pg / L for conjugated CPT and 19.6 pg / L for unconjugated and fully active CPT. For each quantity of lysate used, there was less development activity of topoisomerase I (ie, more superhelical DNA) in the samples from day 2 than in the pre-treatment samples or at day 25. This suggests an inhibitory effect of CRLX101 on these cells at this early time point after administration. The ascites cells were also used for immunohistochemistry (IHC) to assess the levels of topoisomerase I. A basic concordance was observed between the activity assay of topoisomerase I and the IHC of topoisomerase I. As observed in the FIGs. 3A and 3B, there was a reduction of approximately 30% in core staining of ovarian cancer cells isolated from the patient's ascites fluid 2 days after treatment (FIG 3B), compared to a similar sample taken after the administration of the drug (FIG 3A). The decrease in topoisomerase I levels observed directly by IHC in these cells at 48 hours explains why much of the superhelical DNA remains present in FIG routes. 3C with Used reactions on day 2. That is, there is much less enzyme available to act on these substrate molecules.
Summary of Correlative Studies In the Phase I trial reported previously, two dosing schedules were investigated, 3 times a week and week by medium (biweekly). In the program 3 times a week the maximum tolerated dose was approximately 9 mg / m2. The hematological toxicity and cystitis were the DLT in this program.
Non-haematological grade 3/4 adverse events included fatigue in 3 patients (25%), haematuria / dysuria with delayed onset in 2 patients (17%), CPK (creatine phosphokinase) elevated in 1 patient (8%), and dehydration in 1 patient (8%), which were all reversible. Cumulative bladder toxicity in some patients in this program was primarily observed after cycle one and may have been related to the enduring terminal half-life of unconjugated CPT, which is cleared primarily through the kidneys leading to cumulative bladder irritation . Based on this observation, it was decided to investigate a biweekly program as a strategy to reduce cumulative toxicity while maintaining dose administration.
The biweekly program allowed plasma exposure per cycle similar to that achieved in patients but with a significantly reduced incidence of adverse events. The only adverse event of grade 3/4 observed was grade 3 neutropenia in a patient who was reversible. A dose reduction was needed in this program. In this program, CRLX101 was well tolerated without the toxicities normally associated with camptothecin analogues, such as severe diarrhea and hemorrhagic cystitis. It was determined that the BAT in this program was 15 mg / m2.
The pharmacokinetic analysis of CRLX101 was performed after the first dose for all patients. Consistent with the preclinical data, the pharmacokinetics of CRLX101 was characterized by a low volume of distribution and limited systemic clearance. Preclinical studies showed accumulation of CRLX101 in tumors and tissues of the reticuloendothelial system, such as the liver and spleen. An increased release of active CPT from the conjugate in these tissues was also observed. This study also confirmed that the kinetics of CPT release was such that the plasma levels of unconjugated CPT remained significantly below the levels of the conjugate at all time points. After a week, approximately 10% of the maximum recorded concentration of the unconjugated CPT was detected, possibly leading to the cumulative toxicity observed in the program 3 times per week. However, in the biweekly program, levels of unconjugated CPT fell below the limit of quantification before the second dose, which may explain the lack of urinary side effects in this program.
In general, CRLX101 was well tolerated and myelosuppression was DLT. Ten of twenty-four patients demonstrated stable disease on the CT scan evaluation at the end of cycle 2. A patient with pancreatic cancer remained stable for 22.8 months. PK data from serum and urine from all treated patients indicated that the mean half-life elimination for conjugated and unconjugated CPT was 31.8 hr and 43.8 hr, respectively. Cmax and AUCo.nf were linear at all doses and similar when normalized to dose / m2. The biweekly program allowed a plasma exposure to be reached by similar cycle in patients, but with a significantly reduced incidence of adverse events.
Example 2: Synthesis of 6A, 6D-Bis- (2-amino-2-carboxylethylthio) -6A 6D-dideoxy-g-cyclodextrin, 4 (CD-BisCys) Scheme II 4 167 mL of 0.1 M sodium carbonate buffer was degassed for 45 minutes in a 500 mL round bottom flask and 2 necks equipped with a magnetic stir bar, a condenser and a partition. To this solution were added 1.96 g (16.2 mmol) of L-cysteine and 10.0 g (73.8 mmol) of di-odo, deoxy-β-cyclodextrin 2. The resulting suspension was heated to a reflux temperature for 4.5 h until the solution was heated. It turned transparent (colorless). The solution was then cooled to room temperature and acidified to pH 3 using 1N HCl. The product was precipitated by the slow addition of acetone (3 times the weight ratio of the solution). This provided 9.0 g of crude material containing CD-β-scisine (90.0%), unreacted cyclodextrin, CD-mono-cysteine and cystine. The resulting solid was subjected to anion exchange column chromatography (SuperQ650M, Tosoh Bioscience) using gradient elution of 0-0.4M ammonium bicarbonate. All fractions were analyzed by HPLC. The desired fractions were combined and the solvent was reduced to 100 ml_ in vacuo. The final product was precipitated by adding acetone or adding methanol (3 times the weight ratio of the solution). 4 was obtained in 60-90% yield. 1 H NMR (DzO) d 5.08 (m, 7H, CD-2-CH), 3.79-3.94 (m, 30H, CD-3.4-CH, CD-CH2, Cys-CH), 3.49-3.62 (m, 14H, CD-5, 6-CH), 2.92-3.30 (m, 4H, Cys-CH2). 13C NMR (D20) d 172.3, 101.9, 83.9, 81.6, 81.5, 73.3, 72.2, 72.0, 60.7, 54.0; 34.0, 30.6. ESI / MS (m / z): 1342 [M] +, 1364 [M + Na] +. The purity of 4 was confirmed by HPLC.
Example 3: Synthesis of Gly-CPT (Structure 11) (Greenwald et al., Bioorg, Med. Chem., 1998, 6, 551-562) Scheme III eleven I-Boc-glycine (0.9 g, 4.7 mmol) was dissolved in 350 mL of anhydrous methylene chloride at room temperature, and to this solution were added DIPC (0.75 mL, 4.7 mmol), DMAP (382 mg, 3.13 mmol) and camptothecin. (0.55g, 1.57 mmol) at 0 ° C. The reaction mixture was allowed to warm to room temperature and left for 16 h. The solution was washed with 0.1 N HCl and evaporated under reduced pressure to give a white solid, which was recrystallized from methanol to give camptothecin-20-esters of f-Boc-glycine: 1H NMR (D SO-d6) 7.5 -8.8 (m), 7.3 (s) .5.5 (s), 5.3 (s), 4 (m), 2.1 (m), 1.6 (s), 1.3 (d), 0.9 (t). Camptothecin-20-ester of f-Boc-glycine (0.595 g, 1.06 mmol) was dissolved in a mixture of methylene chloride (7.5 ml_) and TFA (7.5 ml_) and stirred at room temperature for 1 h. The solvent was removed and the residue was recrystallized from methylene chloride and ether to give 0.45 g of 11. H NMR (DMSO-d6) 67.7-8.5 (m); 7.2 (s), 5.6 (s), 5.4 (s), 4.4 (m), 2.2 (m), 1.6 (d), 1.0 (t), 13C NMR (DMSO-d6) 6168.6, 166.6, 156.5, 152.2, 147.9, 146.2, 144.3, 131.9, .130.6, 129.7, 128.8, 128.6, 128.0, 127.8, 119.0, 95.0, 77.6, 66.6, 50.5, 47.9, 30.2, 15.9, 7.9. ESI / MS (m / z) expected 405; Found 406 (M + H).
Example 4: Synthesis and Characterization of Copolymers CD-BisCvs-Peg3400 36 and their Conjugates of 37.
A. Synthesis and characterization of CD-BisCys-Peg3400 copolymers 36 Scheme IVa Polii D vs-P -PEGi br. P -. = d 'propanoicamide' ntiie PEO v? G ' Scheme IVb -br E- -i, bijtanokamida. 'P --inlac-j Synthesis of Poly (CDDCys-PA-PEG), 36a 4 (after precipitation with acetone, 63 mg, 0.047 mmol) and PEG-DiSPA (MW 3400, 160 mg, 0.047 mmol) were dried under vacuum for 8 hours. Anhydrous DMSO (1.26 mL) was added to the mixture in argon. After 10 minutes of stirring, anhydrous diisopropylethylamine (DIEA, 2.3 eq.) Was added in argon. The reaction mixture was stirred under argon for 120 h. The polymer containing the solution was dialyzed using 10,000 MWCO of membrane (Spectra / Por 7) against water for 48 h and lyophilized to provide 196 mg 36a (90%, Table 1). Mw = 57.4 kDa, Mn = 41.7 kDa, MJMn = 1.38. 1 H NMR (D 20) d 5.08 (m, CD-2-H), 4.27 (m, Cys-CH), 2.72-3.76 (m, CD-3,4,5,6-CH, CD-CH 2, PEG- CH2), 2.44 (m, Cys-CH2).
Synthesis of another poly (CDDCys-PA-PEG) (36b-f), Poly (CDDCys-BA-PEG) (36g) Poly (CDDCys-CB-PEG) (36h-i) were achieved under polymerization condition similar to that of 36a. The details for the polymerization conditions, monomer selection, polymer molecular weight, polydispersity and yields are listed in Table 6. 36g: 1H NMR (D20) d 5.10 (m, CD-2-H), 4.25-4.37 (m, Cys-CH), 2.72-3.86 (m, CD-3,4,5,6-CH, CD-CH 2, PEG-CH 2), 2.21 (m, Cys-CH 2). 36h-1: NMR (D20) d 5.05 (m, CD-2-H), 4.56 (m, Cys-CH), 2.70-3.93 (m, CD-3,4,5,6-CH, CD- CH2, PEG-CH2), 2.38 (m, -OCH2CH2CH2C (0) -NH-), 2.34 (m, Cys-CH2), 1.90 (m, OCH2CH2CH2C (0) -NH-).
The addition of a non-nucleophilic organic base (such as DIEA) was essential for this polymerization since no change in the viscosity of the polymerization solutions was observed after 48 hours if no base was added. When 2.3 eq. of DIEA, the viscosity of the polymerization solution increased dramatically after 4-6 hours of reaction. DIEA deprotonates the amino groups of 4 to make them more nucleophilic for coupling with PEG-DiSPA. There was no essentially no difference in the polymerizations if other bases were used, such as TEA or DMAP (36b-c, Table 6). The polymerization using 4 recovered by the two different precipitation methods (acetone and methanol) produced polymers with different MW. 4, which was purified by the methanol precipitation method (does not contain free cysteine), gave a higher MW polymer (36d-e) compared to the 4 less pure that was obtained from the acetone precipitation method (36a). Polymerization of 4 with PEG-DiSPA typically produced polymer yields greater than 90%. 4 was polymerized with other activated monomers such as, PEG-DiSBA, PEG-DiBTC and PEG-DiNPC. The reaction of 4 with PEG-DiSBA gave the polymer 36g with unions similar to 36a-f (amide bond, but a -CH2 group more than 36a-f in the linker) with an Mw above 100 kDa, while the reaction of 4 with PEG-DiBTC and PEG-DiNPC generated polymers 36h and 36i, respectively, with part of connecting carbamate and Mw above 50 kDa (Table 6) · Table 6. Polymerization of 4 with dysfunctional PEG. 36ca PEG-DiSPA TEA 120 57.4 42.6 1.35 36d ° PEG-DiSPA DIEA 120 93.6 58.0 1.48 36eD PEG-DiSPA DIEA 144 97.3 58.0 1.67 94 36 ^ PEG-DiSPA DIEA 2 35.3 25.6 1.38 95 36g PEG-DiSBA DIEA 120 114.7 77.9 1.47 96 36h PEG-DiBTC DIEA 120 67.6 39.4 1.47 95 36i PEG-DiNPC DIEA 120 86.5 57.2 1.51 96 to 4 was washed with acetone before polymerization. b 4 was washed with methanol before polymerization.
The polymers 36a-i are highly soluble in aqueous solution. They can be easily dissolved in water or phosphate buffered saline (PBS) in concentrations of at least 200 mg / mL. The solubility of these polymers in aqueous solution in concentrations higher than 200 mg / mL due to the high viscosity was not attempted. These polymers were also soluble in DMF, DMSO and methanol, slightly soluble in CH3CN and CHCI3) but were not soluble in THF and ethyl ether.
Control of Molecular Weight of Polymers CP 4 (After precipitation with methanol) (56.2 mg, 0.0419 mmol) and PEG-DiSPA (147 mg, 0.0419 mmol) were dried under vacuum for 4-8 hours. Dry DMSO (1.1 mL) in argon was added to the mixture. After 10 minutes of stirring, DIEA (16 μl, 2.2 eq.) Was added in argon. A portion of polymerization solution (150 μ?) Was removed and precipitated with ether at selected times (2 h, 18 h, 43 h, 70 h, 168 h and 288 h). MW of the precipitated polymers were determined as described above.
B. Synthesis of Poly conjugates (CDDCys-PA-PEG) -CPT (HGGG6, LGGG10, HG6, HGGG10).
Scheme V Synthesis of Poly (CDDCys-PA-PEG) -GlyGlyGly-CPT (HGGG6) 36e (1.37 g, 0.30 mmol of repeating unit) was dissolved in dry DMSO (136 m! _). The mixture was stirred for 10 minutes. 12 (419 mg, 0.712 mmol, 2.36 eq), DIEA (0.092 mL, 0.712 mmol, 2.36 eq), EDC (172 mg, 0.903 mmol, 3 eq) and NHS (76 mg, 0.662 mmol, 2.2 eq) they were added to the polymer solution and stirred for about 15 hours. The polymer was precipitated with ethyl ether (1 L). The ether was poured and the precipitate was washed with CH 3 CN (3 x 100 ml_). The precipitate was dissolved in 600 ml_ of water. Some of the insoluble solid was filtered through 0.2 μ filters. The solution was dialyzed using 25,000 MWCO of membrane (Spectra / Por 7) for 10 h at 10-15 ° C in DI water. The dialysis water was changed every 60 minutes. The solution of drug conjugate to the polymer was sterilized by passing it through 0.2 μ filters. The solution was lyophilized to give a yellow solid HGGG6 (1.42 g, 85% yield).
Synthesis of Poly (CDDCys-PA-PEG) -GlyGlyGly-CPT (LGGG10) The conjugation of 12 to 36f was carried out in a manner similar to that used to produce HGGG6 except that this conjugate was dialysed with 10,000 MWCO of membrane (Spectra / Per 7) instead of with 25,000 MWCO of membrane. The performance of LGGG10 was 83%.
Synthesis of Poly (CDDCys-PA-PEG) -Gly-CPT (HG6) Conjugation from 11 to 36e was carried out in a manner similar to that used to produce HGGG6. The yield of HG6 was 83%.
Synthesis of Poly (CDDCys-PA-PEG) -GlyGlyGly-CPT (HGGG10) 36e (1.5 g, 0.33 mmol of repeating unit) was dissolved in dry DMSO (150 mL). The mixture was stirred for 10 minutes. 12 (941 mg, 1.49 mmol, 4.5 eq), DIEA (0.258 mL, 1.49 mmol, 4.5 eq), EDC (283 mg, 1.49 mmol, 4.5 eq) and NHS (113 mg, 0.99 mmol, 3 eq) were added to the polymer solution and stirred for approx. 24 hours. Another portion of EDC (142 mg, 0.75 mmol, 2.3 eq) and NHS (56 mg, 0.5 mmol, 1.5 eq) was added to the conjugation solution. The polymer was stirred for an additional 22 hours. The diagnostic procedure was the same as that for the synthesis of HGGG6. The yield of HGGG10 was 77%.
Determination of% in p of CPT in Conjugates Stock solutions of HGGG6, LGGG10, HG6 and HGGG10 were prepared at a concentration of 10 mg / mL in DMSO. An aliquot of stock solution corresponding to 100 g mL was diluted using 1 N NaOH. CPT was completely hydrolysed in this basic solution and transformed into its carboxylate form within 2 h at room temperature. An aliquot of this solution was diluted to 10 μg / mL using 8.5% H3P04 and the CPT carboxylate form was transformed into its lactone form. 30 μL · of this solution was injected into the HPLC. The peak area of the CPT lactone form was integrated and compared to a standard curve. 11 and 12 were conjugated to 36e or 36f (Table 2) using conventional coupling methods. Due to the instability of the ester linker 11 and 12 in aqueous solution, the conjugation was carried out in anhydrous DMSO in argon. It was necessary for an organic base to deprotonate the TFA salts of 11 and 12 to facilitate coupling. For the conjugation of polymers with 12, the loading of the drug by weight percentage (% in p) was about 6-10%. The theoretical maximum drug load is around 13% using PEG with a MW of 3400 Da; the maximum values can be increased by decreasing the MW of the PEG segments. The solubilities of all conjugates in water or PBS were greater than 200 mg / mL (equivalent to 12-20 mg CPT / mL for 6-10% in drug loading p, respectively). The details for HGGG6, LGGG10, HG6 and HGGG10 are summarized in Table 7.
Table 7. Properties of CPT conjugates to the polymer.
Poly Mw conjugate Linked CPT (% M Mnb a main (x 10"3) r in p) HGGG6 97 1 .7 triglycine 6.1 LGGG10 35 1 .6 triglycine 10.2 HG6 97 1 .7 glycine 6.8 HGGG10 97 1 .7 triglycine 9.6 a Abbreviations: H = Large Mw polymer (97 kDa), L = Low Mw polymer (35 kDa), GGG = triglycine linker, G = glycine linker, 6 = drug charge around 6% in p, 10 = Drug loading about 10% on p. b Polydispersity of polymer as measured by light scattering techniques (26) C. CPT release from HGGG6 and HG6 Release of CPT in PBS HGGG6 and HG6 were prepared at 1 mg / mL in PBS (1x, pH 7.4). An aliquot of 100, L of the solution to a 1.5 mL Eppendorf tube and incubated at 37 ° C. The incubated samples were inactivated in time intervals selected and stored at -80 ° C until analysis. Each solution was diluted with 8.5% H3P0 to a total volume of 5 MI in a volumetric flask. 30 μl of each solution was injected into the HPLC. The peak area of the CPT lactone form was integrated and compared to a standard curve.
The analysis for the release of CPT from HGGG6 and HG6 in PBS containing acetylcholinesterase (one esterase, 100 units / m L), in buffer KH2P04 (pH 6.1, 0.1 M) and in the KH2P04 buffer (pH 6.1, 0.1 M) contains cathepsin B (a cysteine proteinase, 200 μ ?, preactivated on ice for 30 minutes in this buffer containing 2 mM DTT and 1 mM EDTA) was carried out in a manner similar to that described above for PBS alone.
Liberation of CPT in Human Plasma An aliquot of stock solution HGGG6 and HG6 was diluted to give the final concentration of 0.5 mg / mL in PBS (1x, pH 7.4). This solution was added to a lyophilized powder of human plasma to reconstitute 100% human plasma in the recommended amount. The solution was divided into an equal volume (250 μm) into 1.5 mL Eppendorf tubes, incubated at 37 ° C and stopped at the selected time point. Samples were stored at -80 ° C until analysis. The samples were separated from the plasma by solid phase extraction columns. The solid phase extraction cartridge (Waters 1cc Oasis HLB cartridge) was preconditioned with 1 mL of acetonitrile and then with 1 mL_ of 8.5% H3PO4 before loading. The samples were acidified with an equal volume of 8.5% H3P04 before loading. After the acidified solution was loaded into the cartridge, the bed was washed with 3 x 1 mL of water. The CPT released and the polymer conjugate were eluted with 3? 1 mL of a mixture of acetonitrile solution and potassium phosphate buffer (pH 4.1) (60/40 v / v). The eluted solution was diluted to 5 mL of total volume in a 5 mL volumetric flask. 30 μL · of each solution was injected into the HPLC. The peak area of the CPT lactone form was integrated and compared to a standard curve.
The release of CPT from HGGG6 and HG6 in PBS containing 4% human plasma (PBS / reconstituted human plasma solution = 96/4 (v / v)), in mouse plasma and in reconstituted human albumin (PBS solution) it was carried out in a manner similar to that described above for pure human plasma.
In PBS (1x, pH 7.4), half-lives (f1 / 2) to release CPT from HG6 and HGGG6 were 59h and 32h, respectively. The half-lives decreased until 25h and 22h, respectively, in the presence of 4% of human plasma, and up to 1.7h and 1.6h, respectively, in 100% of human plasma ("HP") and 2.6h and 2.2h, respectively, in 100 % mouse plasma ("MP"). The rates of CPT release for both HG6 and HGGG6 in the presence of albumin ("Alb") or acetylcholinesterase ("Ac Cho") were in the same order of magnitude as in PBS in a buffer solution at a higher pH under which PBS (pH 6.1) with or without the enzyme cathepsin B (active at pH 6.1), less than 50% of the total conjugated CPT was released from both HG6 and HGGG6 for moments up to 144 h (Table 8).
Table 8. The half-life (fi 2, in hours) of the CPT release from HG6 and HGGG63 pH 6.1 of 4% Cat B Conjugate PBSb HPd MPe Albf Ac Cho9 buffer HPC (pH6.1) ' dor " HG6 59 25 Ti 2 ~ 6 62 33 > 144 > 144 HGGG6 32 22 1.6 2.2 73 43 > 144 > 144 a f1 2 is defined as time (hours) for the release of half of the total conjugated CPT. Abbreviations: HP means human plasma, MP means mouse plasma. b pH 7.4 of 1x PBS buffer c Reconstituted human plasma mixed with PBS (v / v = 4/96) d Reconstituted human plasma e Fresh mouse plasma f In PBS buffer solution of reconstituted human albumin 9 In the presence of PBS acetylcholinesterase solution (100 an idades / μL). n pH 6.1 of phosphate buffer (0.1M) 1 pH 6.1 of phosphate buffer in the presence of cathepsin B Release of CPT in Solution at Different pH.
HGGG6 and HG6 were prepared in 1 mg / mL in buffer with pH ranging from acid (pH = 1.2) to basic (pH = 13.1) and incubated at 37 ° C for 24h. An aliquot of each solution was diluted with 8.5% H3P04 to about 100 g / mL. 30 μl of said solution was injected into the HPLC. The peak area of the CPT lactone form was integrated and compared to a standard curve.
The pH of the aqueous solution has a significant effect on the CPT release rates of both HG6 and HGGG6. The amounts of CPT released from HG6 and HGGG6 at 37 ° C after 24 h in buffer solutions with pH ranging from 1.1 to 13.1 are illustrated in Figure 6. The glycine-bound CPT ester linkages of both HG6 and HGGG6 were very stable at acid pH (1.1 to 6.4) while less than 7% CPT was released in 24 h.
Methods to increase the percentage load of the drug by weight Method I. Synthesis of copolymer C D-BisCvs-Peg with a union of short Peg and its conjugate GlyCPT Example 5: Synthesis of CD-BisCys-Peg (short PEG, for example, Peg200-Peg2000) and its conjugate CPT 42 Scheme VI The syntheses of the polymer and drug conjugate 42 are the same as 36, 37 and 38 While Scheme VI shows that the drug is bound in all available positions, not all positions can be reacted. Therefore, a particle comprising the conjugates described above may include a conjugate that reacted at all available positions for binding and particles that have less than all available positions for the binding containing the drug, eg, the particle it can include a CPD that reacted in one or none of the positions available for the union. Therefore, while Scheme VI describes CPT at each junction point of each polymer subunit, the CDP-CPT conjugate may have less than 2 CPT molecules bound to any given polymer subunit of the CDP. For example, in one embodiment, the CDP-CTP conjugate includes several polymer subunits and each of the polymer subunits can independently include two, one or no CPT bound at each junction point of the polymer subunit. Also, the particles and compositions can include CDP-CPT conjugates having two, one or no CPT bound to each polymer subunit of the CDP-CPT conjugate and the conjugates can also include a mixture of CDP-CPT conjugates which can vary with respect to the amount of CPT bound at each junction point of the polymer subunits of the conjugates in the particle or composition.
Method II. Synthesis of CD-BisCys-Peg Copolymer with Multiple Drug Molecules in each Loading Site.
Example 6: Synthesis of CD-BisCys-Peg and its GluBis conjugate (GlyCPT) 43.
Scheme VII m \ V of PEG = 3400 2 CPT per CD Maximum drug load 13.4 Mw of PEC = Í400 4 CPT per CP Maximum drug load? 36 and Glu-Bis (Gly-CPT) 17 are dissolved in DMSO. EDC (3 eq), NHS (2.2 eq) and DIEA (2.2 eq) are added to the solution. CD-BisCys-Peg-GluBis (GlyCPT) 43 is precipitated with CH3CN and washed with the same solvent until no free drug was detected using UV or TLC. 43 dried under high vacuum. While Scheme VII shows that the drug is bound in all available positions, not all positions can be reacted. Therefore, a particle comprising the conjugates described above may include a conjugate that reacted at all positions available for binding and particles that have less than all available positions for the union containing the drug, e.g., the particle it can include a CDP that reacted in three, two, one or none of the positions available for the union. Therefore, while Scheme VII describes CPT at each junction point of each polymer subunit, the CDP-CPT conjugate may have less than 4 CPT molecules bound to any given polymer subunit of the CDP. For example, in one embodiment, the CDP-CTP conjugate includes several polymer subunits and each of the polymer subunits can independently include four, three, two, one or no CPT bound at each junction point of the polymer subunit. Also, the particles and compositions can include CDP-CPT conjugates having four, three, two, one or no CPT bound to each polymer subunit of the CDP-CPT conjugate, and the conjugates can also include a mixture of CDP-conjugates. CPT that may vary with respect to the amount of CPT bound at each junction point of the polymer subunits of the conjugates in the particle or composition.
Example 7: Synthesis and Analysis n Vitro of CDP-Gly-SN-38 SN-38 was derived with the amino acid glycine at the 20-OH position as shown in Scheme VIII. Briefly, 20 (S) -7-ethyl-10-hydroxycamptothecin (SN-38, 1.0g, 2.5 mmol) was dissolved in a mixture of 70 mL of dimethylformamide (DMF) and 30 mL of pyridine. A solution of di-tert-butyl-dicarbonate (0.83 g, 3.8 mmol) in 10 mL of DMF was added and the mixture was stirred at room temperature overnight (12 hours). The solvent was removed in vacuo to give a yellow solid and recrystallized from boiling 2-propanol (75 mL) to give 20 (s) ÷ 10-tert-butoxycarbonyloxy-7-ethyl-camptothecin (Boc-SN-38 ) as a yellow solid (0.6 g, 48% yield).
Boc-SN-38 (0.73g, 1.5 mmol), N- (tert-butoxycarbonyl) glycine (0.26g, 1.5 mmol) and 4-dimethylaminopyridine (DMAP, 0.18g, 1.5 mmol) were dissolved in anhydrous methylene chloride (30 mL). and cooled to 0 ° C. 1,3-Diisopropyl-carbodiimide (DIPC, 0.19g, 1.5 mmol) was added, the mixture was stirred at 0 ° C for 30 minutes followed by stirring for 4 hours at room temperature. The mixture was diluted with methylene chloride to 100 mL, washed twice with an aqueous solution of 0.1N hydrochloric acid (25 mL), dried over magnesium sulfate and the solvent removed in vacuo. The resulting yellow solid was purified by chromatography Instantaneous in methylene chloride: acetone (9: 1) followed by removal of the solvent in vacuo to provide 20-O- (N- (tert-bu toxic rbonyl) glycyl) -10-tert-butyloxycarbonyloxy-7-ethylcamptothecin ( diBoc-Gly-SN-38, 640 mg, 67% yield).
Scheme VIII: Derivation of SN-38 to 20-O- (N- (tert-butoxycarbonyl) glycyl) -10-tert-butyloxycarbonyloxy-7-ethylcamptothecin (diBOC-Gly-SN-38) The CDP was synthesized as described previously (Cheng et al. (2003) Bioconjugate Chemistry 14 (5): 1007-1017). DiBOC-Gly-SN-38 (0.62g, 0.77 mmol) was deprotected in 15 mL of a 1: 1 mixture of methylene chloride: trifluoroacetic acid (TFA) at room temperature for 1 hour. 20-O-trifluoroglycine-10-hydroxy-7-ethylcamptotecin was isolated (TFA-Gly-SN-38, 0.57g, 97% of yield) as a yellow solid by ethanol precipitation (100 mL), followed by two washes with ethanol (30 mL each), dissolution in methylene chloride and removal of the solvent in vacuo. ESI / MS expected 449.4; Found 471.66 (M + Na).
CDP-Gly-SN-38 (Poly-CD-PEG-Gly-SN-38, Scheme IX) was synthesized in the following manner: CDP (270 mg, 0.056 mmol), TFA-Gly-SN-38 (70 mg, 0.12 mmol), N-hydroxy-succinimide (14 mg, 0.12 mmol) and -ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI, 32 mg, 0.17 mmol) in dimethylformamide (10 mL) and stirred for 4 hours. hours at room temperature. The polymer was precipitated by the addition of 50 mL of acetone followed by 50 mL of diethyl ether. The precipitate was centrifuged, washed twice with 20 mL of acetone each and dissolved in acidified water until pH 3.0 with hydrochloric acid. The polymer solution was dialysed 24 hours against pH 3.0 of water using 25 kDa MWCO dialysis membrane. The resulting solution was lyophilized to provide CDP-Gly-SN-38 (180 mg, 67% yield). The polymer was analyzed for a free and total SN-38 content by HPLC using SN-38 as a standard curve as described above (Cheng et al. (2003) Bioconjugate Chemistry 14 (5): 1007-1017). The content of total SN-38 was 7.66% w / w of which 97.4% was bound to the polymer. The average particle size was determined to be 27.9 nm by dynamic light scattering.
Scheme IX: Structure of a subunit of DP-Gly-SN-38 While Scheme IX shows that the drug is bound in all positions available in the subunit, not all positions can be reacted. Therefore, a particle comprising the conjugates described above can include a conjugate that reacted in all available positions for binding and particles that have less than all available positions for the union containing the drug, for example, the particle may include a CPD that reacted in one or none of the positions available for the union. Therefore, while Scheme IX describes SN-38 at each junction point of each polymer subunit, the CDP-SN-38 conjugate may have less than 2 SN-38 molecules bound to any given polymer subunit of the CDP. . For example, in one embodiment, the CDP-SN-38 conjugate includes several polymer subunits and each of the polymer subunits can independently include two, one or no CPT bound at each junction point of the polymer subunit. Also, the particles and compositions can include CDP-SN-38 conjugates having two, one or no CPT bound to each polymer subunit of the CDP-Sn-38 conjugate and the conjugates can also include a mixture of CDP-conjugates Sn-38 which may vary with respect to the amount of Sn-38 bound at each junction of the polymer subunits of the conjugates in the particle or composition.
In vitro evaluation of CDP-Gly-SN-38 CDP-Gly-SN-38 was evaluated in human ovarian cancer cell lines A2780 in vitro as follows: Human cells of the A2780 ovarian carcinoma were obtained from the American Type Culture Collection. Cells were plated in 96-well plates at a concentration of 5,000 cells per well and cultured in medium containing 10% fetal bovine serum at 37 ° C for 24 h in a humid atmosphere of 5% C02. The medium was replaced with fresh medium containing the test compound at concentrations ranging from 0.01 nmol / L to 1 pmol / L. Triple wells were treated per plate in each concentration. The controls were cells treated with vehicle and medium only in white. Plates were incubated at 37 ° C for 72 h. The MTS assay reagent was prepared by diluting an aqueous solution CelITiter 96 (Promega) 5 times in PBS / glucose (4.5 g / L). The cell culture medium was aspirated and 100 μ? of MTS reagent to each well. Plates were incubated at 37 ° C for 1 h. The plates were shaken for 5 min and the absorbance was measured at 485 nm using a SPECTRAFluor Plus reading plate (Tecan). The percentage of cell survival was calculated with respect to the untreated cells, and the IC 50 of the logarithmic dose plots (nmol / L) were estimated in comparison with% cell survival (GraphPad Prizm).
The results of this experiment are shown in Table 9 below.
Table 9: IC50 of SN-38 and CDP-Gly-SN-38 in ovarian cells A2780.
Other modalities are found in the claims.

Claims (35)

REIVI DICACIONES
1. A method for treating a proliferative disorder in a subject, comprising: providing at least one treatment cycle with a composition comprising CRLX101, wherein the cycle comprises the following administrations: providing an initial administration of a composition comprising CRLX101 to said subject with a dosage greater than 12 mg / m2, for example, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2 , wherein said dosage is expressed in mg of camptothecin, as opposed to mg of the conjugate, optionally, providing one or more subsequent administrations of said CRLX101, with a dosage greater than 12 mg / m2, for example, 13 mg / m2, 14 mg m2, 15 mg / m2, 16 mg / m2 or 17 mg / m2, in where each subsequent administration is provided, independently between 9, 10, 11, 12, 13, 14 or 15 days after the previous administration, to treat the proliferative disorder like this.
2. The method of claim 1, wherein the cancer is lung cancer, for example, non-microcytic lung cancer, for example, non-small cell lung cancer of squamous cells.
3. The method of claim 2, wherein the subject has a mutation in the KRAS gene and / or has increased levels of KRAS expression, for example, as compared to a reference standard.
4. The method of claim 2 or 3, wherein the subject has a mutation in the EGFR gene.
5. The method of claim 1, wherein the cancer is an ovarian cancer.
6. The method of claim 5, wherein the cancer is insensitive, unruly or resistant to a chemotherapeutic agent, for example, a platinum-based agent (e.g., carboplatin, cisplatin, oxaliplatin).
7. The method of claim 5 or 6, wherein the subject is administered CRLX101 in combination with a second chemotherapeutic agent.
8. The method of claim 1, wherein the CRLX101 is administered by intravenous administration for a period equal to or less than 30 minutes, 45 minutes, 60 minutes or 90 minutes.
9. The method of claim 1, wherein CRLX1I01 is administered by intravenous administration for a period of 12 hours, 15 hours, 18 hours, 20 hours, 21 hours, 24 hours or 27 hours.
10. A method for treating a proliferative disorder, eg, cancer, in a subject, comprising: providing at least one treatment cycle with a composition comprising CRLX101, wherein the cycle comprises the following administrations: providing an initial administration of a composition comprising CRLX101 to said subject with a dosage greater than 6 mg / m2, for example, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2 or 12 mg / m2, wherein said dosage is expressed in mg of camptothecin, as opposed to mg of the conjugate, twice a day, optionally, providing one or more subsequent administrations of said CRLX101, with a dosage greater than 6 mg / m2 , for example, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2 or 12 mg / m2 twice a day, wherein said dosage is expressed in mg of camptothecin, in opposition to mg of the conjugate, wherein each subsequent administration is provided, independently, between 9, 10, 11, 12, 13, 14 or 15 days after the previous administration, to treat the proliferative disorder like this.
11. A method for treating a cancer in a subject, said method comprises: provide an initial administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP to said subject in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 , 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2 , 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2 , wherein said dosage is expressed in mg of the topoisomerase inhibitor, as opposed to mg of the conjugate and optionally, providing one or more subsequent administrations of said conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2 m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2 or 30 mg / m2 m2, where each subsequent dosage is provided, independently, between 9, 10, 11, 12, 13, 14, 15 or 16 days after the previous administration to treat cancer.
12. The method of claim 11, wherein the dosage of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15 or 20 administrations is the same.
13. The method of claim 11 or 12, wherein the time between at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15 or 20 administrations is the same.
14. The method of any of claims 11-13, wherein each subsequent administration is administered 12-16 days after the previous administration.
15. The method of any of claims 11-14, wherein the drug is provided at 12-17 mg / m2 / administration.
16. The method of any of claims 11-15, wherein the conjugate includes an inhibitor of topoisomerase I and / or a topoisomerase II inhibitor.
17. The method of claim 16, wherein the conjugate includes camptothecin, irinotecan, SN-38, topotecan, lamelarin D or derivatives thereof.
18. The method of any of claims 11-17, wherein the conjugate is administered by intravenous administration for a period equal to or less than about 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes or 180 minutes.
19. The method of any of claims 11-18, wherein the cancer is lung cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, colorectal cancer or renal cancer.
20. The method of any of claims 11-19, wherein the conjugate is administered in combination with one or more additional chemotherapeutic agents.
21. A method for treating a cancer in a subject, said method comprises: provide an initial administration of a conjugate, particle or composition of the topoisomerase inhibitor attached to the CDP to said subject in a dosage of 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2 , 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / m2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2 , 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2, 30 mg / m2, 31 mg / m2, 32 mg / m2, 33 mg / m2 , 34 mg / m2, 35 mg / m2 or 36 mg / m2, wherein said dosage is expressed in mg of the topoisomerase inhibitor, as opposed to mg of the conjugate and optionally, provide one or more subsequent administrations of said conjugate, particle or composition of the topoisomerase inhibitor bound to CDP in a dosage of 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2, 11 mg / m2, 12 mg / m2, 13 mg / m2, 14 mg / m2, 15 mg / m2, 16 mg / m2, 17 mg / m2, 18 mg / m2, 19 mg / rn2, 20 mg / m2, 21 mg / m2, 22 mg / m2, 23 mg / m2, 24 mg / m2, 25 mg / m2, 26 mg / m2, 27 mg / m2, 28 mg / m2, 29 mg / m2, 30 mg / m2, 3 1 mg / m2, 32 mg / m2, 33 mg / m2, 34 mg / m2, 35 mg / m2 or 36 mg / m2, wherein each subsequent administration is provided, independently, between 17, 18, 19, 20 , 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 days after the previous administration to treat cancer.
22. A method for treating a cancer in a subject, said method comprises: providing an initial administration of a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP, eg, a conjugate, particle or composition; of camptothecin or camptothecin derivative linked to the CDP to the subject in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2, wherein the dosage is expressed in mg of the topoisomerase inhibitor, as opposed to the mg of the conjugate, optionally, providing one or more subsequent administrations of said conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP in a dosage of 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, 10 mg / m2 or 11 mg / m2, where each subsequent administration is provided, independently, between 5, 6, 7, 8, 9 days after the previous administration to treat cancer like that.
23. A method for treating ovarian cancer in a subject, said method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP to a subject in combination with a second chemotherapeutic agent.
24. A method for treating colorectal cancer in a subject, said method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the C DP to a subject in combination with a second chemotherapeutic agent.
25. A method for treating lung cancer in a subject, said method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP to the subject.
26. A method for treating lung cancer in a subject, said method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the C DP to the subject in combination with a second chemotherapeutic agent.
27. A method for treating breast cancer in a subject, said method comprises administering to a subject a conjugate, particle or composition of the topoisomerase inhibitor bound to the C D P, in combination with a second therapeutic agent.
28. A method for treating gastric cancer in a subject, said method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the C DP to the subject in combination with a second myotherapeutic agent.
29. A method for treating a cancer in a subject, said method comprises administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CD P to the subject in combination with an inhibitor of angiogenesis.
30. The method of claim 29, wherein the cancer is renal cancer.
31 The method of claim 29 or 30, wherein the inhibitor of angiogenesis is an inhibitor of the VEG F pathway.
32. A method for treating a cancer in a subject, said method comprises administering a polysaccharide to said subject; and administering a conjugate, particle or composition of the topoisomerase inhibitor bound to the CDP to the subject.
33. A method for treating a cancer in a subject, said method comprising administering an agent that improves the bladder toxicity associated with the therapy to the subject; and administering a composition comprising a camptothecin or camptothecin derivative to the subject.
34. A method for treating a cancer in a subject, said method comprises: provide a subject who has a cancer, and who has been administered an agent that reduces or inhibits one or more symptoms of his / her persistency and administering a composition comprising a conjugate, particle or composition of the topoisomerase inhibitor umido to CDP to the subject.
35. A method to treat a subject with a cancer, said method comprises: selecting a subject having a cancer that has increased KRAS and / or ST expression levels; Y administering a conjugate, particle or composition of the i nhiomer of the topoisomerase attached to the CDP, to the subject in an effective amount to treat the cancer, to thereby treat the cancer.
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